Archive for the ‘Cardiac Stem Cells’ Category

SYDNEY, Oct. 5, 2021 /PRNewswire/ -- Clinical stage drug development company Pharmaxis Ltd (ASX: PXS) today announced further positive results of data analysis from a phase 1c clinical trial (MF-101) studying its drug PXS-5505 in patients with the bone marrow cancer myelofibrosis for 28 days at three dosage levels.

Assessment with Pharmaxis' proprietary assays of the highest dose has shown inhibition of the target enzymes, LOX and LOXL2, at greater than 90% over a 24-hour period at day 7 and day 28. The trial safety committee has reviewed the results and having identified no safety signals, has cleared the study to progress to the phase 2 dose expansion phase where 24 patients will be treated at the highest dose twice a day for 6 months.

Pharmaxis CEO Gary Phillips said, "We are very pleased to have completed the dose escalation phase of this study with such clear and positive findings.We will now immediately progress to the phase 2 dose expansion study where we aim to show PXS-5505 is safe to be taken longer term with the disease modifying effects that we have seen in the pre-clinical models. The trial infrastructure and funding is in place and we are on track to complete the study by the end of 2022."

Independent, peer-reviewed research has demonstrated the upregulation of several lysyl oxidase family members in myelofibrosis.The level of inhibition of LOX achieved in the current study at all three doses significantly exceeds levels that caused disease modifying effects with PXS-5505 in pre-clinical models of myelofibrosis with improvements in blood cell count, diminished spleen size and reduced bone marrow fibrosis. LOXL2 was inhibited to a similar degree and based on pre-clinical work such high inhibition is likely replicated for other LOX family members (LOXL1, 3 and 4).[1] Study data can be viewed in the full announcement.

Commenting on the results of the trial, Dr Gabriela Hobbs, Assistant Professor, Medicine, Harvard Medical School & Clinical Director, Leukaemia, Massachusetts General Hospital said, "Despite improvements in the treatment of myelofibrosis, the only curative therapy remains an allogeneic stem cell transplantation, a therapy that many patients are not eligible for due to its morbidity and mortality. None of the drugs approved to date consistently or meaningfully alter the fibrosis that defines this disease. PXS-5505 has a novel mechanism of action by fully inhibiting all LOX enzymes. An attractive aspect of this drug is that so far in healthy controls and in this phase 1c study in myelofibrosis patients, the drug appears to be very well tolerated. This is meaningful as approved drugs and those that are undergoing study, are associated with abnormal low blood cell counts. Preliminary data thus far, demonstrate that PXS-5505 leads to a dramatic, >90% inhibition of LOX and LOXL2 at one week and 28 days. This confirms what's been shown in healthy controls as well as mouse models, that this drug can inhibit the LOX enzymes in patients. Inhibiting these enzymes is a novel approach to the treatment of myelofibrosis by preventing the deposition of fibrosis and ultimately reversing the fibrosis that characterizes this disease."

The phase 1c/2a trial MF-101 cleared by the FDA under the Investigational New Drug (IND) scheme aims to demonstrate that PXS-5505, the lead asset in Pharmaxis' drug discovery pipeline, is safe and effective as a monotherapy in myelofibrosis patients who are intolerant, unresponsive or ineligible for treatment with approved JAK inhibitor drugs. Trial sites will now open to recruit myelofibrosis patients into the 6-month phase 2 study in Australia, South Korea, Taiwan and the USA.

An effective pan-LOX inhibitor for myelofibrosis would open a market that is conservatively estimated at US$1 billion per annum.

While Pharmaxis' primary focus is the development of PXS-5505 for myelofibrosis, the drug also has potential in several other cancers including liver and pancreatic cancer where it aims to breakdown the fibrotic tissue in the tumour and enhance the effect of chemotherapy treatment.

Trial Design

Name of trial

PXS5505-MF-101: A phase 1/2a study to evaluate safety, pharmacokinetic and pharmacodynamic dose escalation and expansion study of PXS-5505 in patients with primary, post-polycythaemia vera or post-essential thrombocythemia myelofibrosis

Trial number

NCT04676529

Primary endpoint

To determine the safety of PXS-5505 in patients with myelofibrosis

Secondary endpoints

Blinding status

Open label

Placebo controlled

No

Trial design

Randomised, multicentre, 4 week duration phase 1 (dose escalation) followed by 6 month phase 2 (dose expansion)

Treatment route

Oral

Treatment frequency

Twice daily

Dose level

Dose escalation: three escalating doses

Dose expansion: one dose

Number of subjects

Dose escalation: minimum of three patients to maximum of 18 patients

Dose expansion: 24 patients

Subject selection criteria

Patients with primary or secondary myelofibrosis who are intolerant, unresponsive or ineligible for treatment with approved JAK inhibitor drugs

Trial locations

Dose escalation: Australia (2 sites) and South Korea (4 sites)

Dose expansion: Australia, Korea, Taiwan, USA

Commercial partners involved

No commercial partner

Reference: (1) doi.org/10.1002/ajh.23409

AUTHORISED FOR RELEASE TO ASX BY:

Pharmaxis Ltd Disclosure Committee. Contact: David McGarvey, Chief Financial Officer and Company Secretary: T +61 2 9454 7203, E david.mcgarvey@pharmaxis.com.au

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About Pharmaxis

Pharmaxis Ltd is an Australian clinical stage drug development company developing drugs for inflammatory and fibrotic diseases, with a focus on myelofibrosis. The company has a highly productive drug discovery engine built on its expertise in the chemistry of amine oxidase inhibitors, with drug candidates in clinical trials. Pharmaxis has also developed two respiratory products which are approved and supplied in global markets, generating ongoing revenue.

Pharmaxis is developing its drug PXS-5505 for the bone marrow cancer myelofibrosis which causes a build up of scar tissue that leads to loss of production of red and white blood cells and platelets. The US Food and Drug Administration has granted Orphan Drug Designation to PXS-5055 for the treatment of myelofibrosis and permission under an Investigational Drug Application (IND) to progress a phase 1c/2 clinical trial that began recruitment in Q1 2021. PXS5505 is also being investigated as a potential treatment for other cancers such as liver and pancreatic cancer.

Other drug candidates being developed from Pharmaxis' amine oxidase chemistry platform are targeting fibrotic diseases such as kidney fibrosis, NASH, pulmonary fibrosis and cardiac fibrosis; fibrotic scarring from burns and other trauma; and inflammatory diseases such as Duchenne Muscular Dystrophy.

Pharmaxis has developed two products from its proprietary spray drying technology that are manufactured and exported from its Sydney facility; Bronchitol for cystic fibrosis, which is approved and marketed in the United States, Europe, Russia and Australia; and Aridol for the assessment of asthma, which is approved and marketed in the United States, Europe, Australia and Asia.

Pharmaxis is listed on the Australian Securities Exchange (PXS). Its head office, manufacturing and research facilities are in Sydney, Australia. http://www.pharmaxis.com.au

About PXS-5505

PXS-5505 is an orally taken drug that inhibits the lysyl oxidase family of enzymes, two members LOX and LOXL2 are strongly upregulated in human myelofibrosis. In pre-clinical models of myelofibrosis PXS-5505 reversed the bone marrow fibrosis that drives morbidity and mortality in myelofibrosis and reduced many of the abnormalities associated with this disease. It has already received IND approval and Orphan Drug Designation from the FDA.

Myelofibrosis is a disorder in which normal bone marrow tissue is gradually replaced with a fibrous scar-like material. Over time, this leads to progressive bone marrow failure. Under normal conditions, the bone marrow provides a fine network of fibres on which the stem cells can divide and grow. Specialised cells in the bone marrow known as fibroblasts make these fibres.

In myelofibrosis, chemicals released by high numbers of platelets and abnormal megakaryocytes (platelet forming cells) over-stimulate the fibroblasts. This results in the overgrowth of thick coarse fibres in the bone marrow, which gradually replace normal bone marrow tissue. Over time this destroys the normal bone marrow environment, preventing the production of adequate numbers of red cells, white cells and platelets. This results in anaemia, low platelet counts and the production of blood cells in areas outside the bone marrow for example in the spleen and liver, which become enlarged as a result.

Myelofibrosis can occur at any age but is usually diagnosed later in life, between the ages of 60 and 70 years. The cause of myelofibrosis remains largely unknown. It can be classified as either JAK2 mutation positive (having the JAK2 mutation) or negative (not having the JAK2 mutation).

Source: Australian Leukemia Foundation: https://www.leukaemia.org.au/disease-information/myeloproliferative-disorders/types-of-mpn/primary-myelofibrosis/

Forward-looking statements

Forwardlooking statements in this media release include statements regarding our expectations, beliefs, hopes, goals, intentions, initiatives or strategies, including statements regarding the potential of products and drug candidates. All forward-looking statements included in this media release are based upon information available to us as of the date hereof. Actual results, performance or achievements could be significantly different from those expressed in, or implied by, these forward-looking statements. These forward-looking statements are not guarantees or predictions of future results, levels of performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this document. For example, despite our efforts there is no certainty that we will be successful in developing or partnering any of the products in our pipeline on commercially acceptable terms, in a timely fashion or at all. Except as required by law we undertake no obligation to update these forward-looking statements as a result of new information, future events or otherwise.

CONTACT:

Media: Felicity Moffatt: T +61 418 677 701, E felicity.moffatt@pharmaxis.com.au

Investor relations:Rudi Michelson (Monsoon Communications) T +61 411 402 737, E rudim@monsoon.com.au

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Pharmaxis Cleared To Progress To Phase 2 Bone Marrow Cancer Trial - WAGM

Shahid Akhter, editor, ETHealthworld spoke to Dr. Dinesh Bhurani, Director, Department of Hemato-Oncology & Bone Marrow Transplant, Rajiv Gandhi Cancer Institute and Research Centre, to know about the progress of NPRD and the challenges associated with blood stem cell transplants.

How do you think the National Policy for Rare Diseases will impact the treatment of patients suffering from rare blood disorders? Will it help reduce the lag that we often see in policy and practice when it comes to healthcare systems?National Policy on Rare Diseases is a step-in right direction and must be welcomed by the Indian medical fraternity. It not only recognizes rare diseases for the first time in India but also has brought forward the possibility of affordable treatment for life-threatening rare diseases which were not previously covered under the national health program. The policy advocates access for treatment through center of excellences, crowd funding and financial assistance.

The NPRD in a bid to enable patients suffering from rare blood disorders has laid emphasis on the option of one-time curative treatment through hematopoietic stem cell transplant for diseases such as Severe Combined Immunodeficiency (SCID), Chronic Granulomatous disease, Wiskott Aldrich Syndrome, Osteopetrosis, and Fanconi Anaemia. By committing to provide a Rs. 20 lakhs cover for the one-time treatment cost of diseases falling under Group 1 through the umbrella scheme of Rashtriya Arogya Nidhi, the NPRD has attempted to provide coverage to almost 40 per cent of the population who are eligible under the Pradhan Mantri Jan Arogya Yojana. The NPRD as a policy that advocates affordable and accessible healthcare and has the potential to lead to the creation of a conducive healthcare ecosystem whereby multisectoral partnerships can collaboratively work towards reduction in the lag between policy and practice often seen otherwise, thereby leading people to live healthier and fuller lives.

Another reason for low number of donors in India is the misconception that stem cell donation comes with a cost to donor. This idea is completely misplaced and untrue as the cost of procedure starting from sample collection, donation and travel is free of cost, and covered under the cost of treatment of a patient for whom the donation is needed. Added to this is the fact that the number of organizations working in the country in the space of blood stem cell transplant is limited at best, thus awareness generation as compared to other health issues is nominal. However, the situation is gradually evolving and ICMR in its 2021 guidelines has gone on to recognize seven registries across the country as active stakeholders in this ecosystem. This recognition by ICMR will hopefully lead to greater awareness generation.

For blood stem cell transplant knowledge is key in establishing patient donor linkage, and by storing the requisite information with them, these registries do just that. Technology is a tool that has been successfully leveraged by stakeholders in the ecosystem to establish linkages. The Hap- E Search is one such tool that has been used by hospitals in the country to find donor matches for their patients. This software is perhaps one of the most enabling tools available to us in the ecosystem, as it helps find HLA matches not just in the country but across the world. This software is now being used by many government hospitals like AIIMS, Delhi and PGIMER Chandigarh. Once the matching donor is found via the HAP-E Search, the donor is encouraged to make the donation, provided counselling and support to donate blood stem cells, and post donation the stem cells are transported to the patients location.

The NPRD proposed crowdfunding and PPP models to ensure more patients availing treatment for rare diseases. How beneficial do you think such partnerships can be to enable blood stem cell transplant ecosystem?Treatment for rare diseases has been found to be expensive across the world. It is thus that despite stem cell transplants being a proven effective solution in the case of some blood disorders, affordability continues to be a challenge for patients and their families. With treatment costs ranging anywhere between Rs. 15-45 lakh, it remains out of reach for most patients in the country. Also, blood disorders, classified as rare, have limited infrastructure in health systems, networks, and subsidies for patients to access treatments are few. In such a scenario, crowdfunding is definitely a feasible option for patients that would ensure that they do not have to forego treatment due to a paucity of resources.

As per the NPRD, the money raised through crowdfunding would directly get credited to the treatment centre thus ensuring that there is adequate linkage. Further, the public private partnership model suggested by the government has enabled it to avail the support of non- governmental and not-for- profit agencies present in the country. This is truly commendable as not only will this ensure more patient donor linkage in the blood stem transplant ecosystem but will also lead to greater awareness generation and registrations of donors as well. One significant organization that has already partnered with the government in this arena is the DKMS BMST Foundation India. With over 50,000 blood stem cell donors registered with them, this organization has been steadily working towards enabling the ecosystem. In the case of rare diseases, it is imperative that stakeholders do not work in isolation and the government working alongside the private can lead to greater hope for many patients with greater amenities and facilities for treatment being made accessible to them.

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Lack of awareness about blood stem cell donation is one of the leading causes for low number of donors in In.. - ETHealthworld.com

DBMR has added another report named Exosome therapeutic Market with information Tables for recorded and figure years addressed with Chats and Graphs spread through Pages with straightforward definite examination. The a-list report concentrates on broad assessment of the market development expectations and limitations. The systems range from new item dispatches, extensions, arrangements, joint endeavors, organizations, to acquisitions. This report includes profound information and data on what the markets definition, characterizations, applications, and commitment and furthermore clarifies the drivers and restrictions of the market which is gotten from SWOT investigation. Worldwide market examination report serves a great deal for the business and presents with answer for the hardest business questions. While making Exosome therapeutic Market report, examination and investigation has been completed with one stage or the mix of a few stages relying on the business and customer necessities.

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Global Exosome Therapeutic Market By Type (Natural Exosomes, Hybrid Exosomes), Source (Dendritic Cells, Mesenchymal Stem Cells, Blood, Milk, Body Fluids, Saliva, Urine Others), Therapy (Immunotherapy, Gene Therapy, Chemotherapy), Transporting Capacity (Bio Macromolecules, Small Molecules), Application (Oncology, Neurology, Metabolic Disorders, Cardiac Disorders, Blood Disorders, Inflammatory Disorders, Gynecology Disorders, Organ Transplantation, Others), Route of administration (Oral, Parenteral), End User (Hospitals, Diagnostic Centers, Research & Academic Institutes), Geography (North America, Europe, Asia-Pacific and Latin America)

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Exosome therapeutic market is expected to gain market growth in the forecast period of 2019 to 2026. Data Bridge Market Research analyses that the market is growing with a CAGR of 21.9% in the forecast period of 2019 to 2026 and expected to reach USD 31,691.52 million by 2026 from USD 6,500.00 million in 2018. Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

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Exosomes are used to transfer RNA, DNA, and proteins to other cells in the body by making alteration in the function of the target cells. Increasing research activities in exosome therapeutic is augmenting the market growth as demand for exosome therapeutic has increased among healthcare professionals.

Increased number of exosome therapeutics as compared to the past few years will accelerate the market growth. Companies are receiving funding for exosome therapeutic research and clinical trials. For instance, In September 2018, EXOCOBIO has raised USD 27 million in its series B funding. The company has raised USD 46 million as series a funding in April 2017. The series B funding will help the company to set up GMP-compliant exosome industrial facilities to enhance production of exosomes to commercialize in cosmetics and pharmaceutical industry.

Increasing demand for anti-aging therapies will also drive the market. Unmet medical needs such as very few therapeutic are approved by the regulatory authority for the treatment in comparison to the demand in global exosome therapeutics market will hamper the market growth market. Availability of various exosome isolation and purification techniques is further creates new opportunities for exosome therapeutics as they will help company in isolation and purification of exosomes from dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, and urine and from others sources. Such policies support exosome therapeutic market growth in the forecast period to 2019-2026.

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Competitive Landscape and Exosome Therapeutic Market Share Analysis

Global exosome therapeutic market competitive landscape provides details by competitor. Details included are company overview, company financials, revenue generated, market potential, investment in research and development, new market initiatives, global presence, production sites and facilities, company strengths and weaknesses, product launch, product trials pipelines, concept cars, product approvals, patents, product width and breadth, application dominance, technology lifeline curve. The above data points provided are only related to the companys focus related to global exosome therapeutic market.

The major players covered in the report are evox THERAPEUTICS, EXOCOBIO, Exopharm, AEGLE Therapeutics, United Therapeutics Corporation, Codiak BioSciences, Jazz Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH, ReNeuron Group plc, Capricor Therapeutics, Avalon Globocare Corp., CREATIVE MEDICAL TECHNOLOGY HOLDINGS INC., Stem Cells Group among other players domestic and global. Exosome therapeutic market share data is available for Global, North America, Europe, Asia-Pacific, and Latin America separately. DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

Many joint ventures and developments are also initiated by the companies worldwide which are also accelerating the global exosome therapeutic market.

For instance,

Partnership, joint ventures and other strategies enhances the company market share with increased coverage and presence. It also provides the benefit for organisation to improve their offering for exosome therapeutics through expanded model range.

Global Exosome Therapeutic Market Scope and Market Size

Global exosome therapeutic market is segmented of the basis of type, source, therapy, transporting capacity, application, route of administration and end user. The growth among segments helps you analyse niche pockets of growth and strategies to approach the market and determine your core application areas and the difference in your target markets.

Based on type, the market is segmented into natural exosomes and hybrid exosomes. Natural exosomes are dominating in the market because natural exosomes are used in various biological and pathological processes as well as natural exosomes has many advantages such as good biocompatibility and reduced clearance rate compare than hybrid exosomes.

Exosome is an extracellular vesicle which is released from cells, particularly from stem cells. Exosome functions as vehicle for particular proteins and genetic information and other cells. Exosome plays a vital role in the rejuvenation and communication of all the cells in our body while not themselves being cells at all. Research has projected that communication between cells is significant in maintenance of healthy cellular terrain. Chronic disease, age, genetic disorders and environmental factors can affect stem cells communication with other cells and can lead to distribution in the healing process. The growth of the global exosome therapeutic market reflects global and country-wide increase in prevalence of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases, along with increasing demand for anti-aging therapies. Additionally major factors expected to contribute in growth of the global exosome therapeutic market in future are emerging therapeutic value of exosome, availability of various exosome isolation and purification techniques, technological advancements in exosome and rising healthcare infrastructure.

Rising demand of exosome therapeutic across the globe as exosome therapeutic is expected to be one of the most prominent therapies for autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases treatment, according to clinical researches exosomes help to processes regulation within the body during treatment of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases. This factor has increased the research activities in exosome therapeutic development around the world for exosome therapeutic. Hence, this factor is leading the clinician and researches to shift towards exosome therapeutic. In the current scenario the exosome therapeutic are highly used in treatment of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases and as anti-aging therapy as it Exosomes has proliferation of fibroblast cells which is significant in maintenance of skin elasticity and strength.

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Exosome therapeutic Market Country Level Analysis

The global exosome therapeutic market is analysed and market size information is provided by country by type, source, therapy, transporting capacity, application, route of administration and end user as referenced above.

The countries covered in the exosome therapeutic market report are U.S. and Mexico in North America, Turkey in Europe, South Korea, Australia, Hong Kong in the Asia-Pacific, Argentina, Colombia, Peru, Chile, Ecuador, Venezuela, Panama, Dominican Republic, El Salvador, Paraguay, Costa Rica, Puerto Rico, Nicaragua, Uruguay as part of Latin America.

Country Level Analysis, By Type

North America dominates the exosome therapeutic market as the U.S. is leader in exosome therapeutic manufacturing as well as research activities required for exosome therapeutics. At present time Stem Cells Group holding shares around 60.00%. In addition global exosomes therapeutics manufacturers like EXOCOBIO, evox THERAPEUTICS and others are intensifying their efforts in China. The Europe region is expected to grow with the highest growth rate in the forecast period of 2019 to 2026 because of increasing research activities in exosome therapeutic by population.

The country section of the report also provides individual market impacting factors and changes in regulation in the market domestically that impacts the current and future trends of the market. Data points such as new sales, replacement sales, country demographics, regulatory acts and import-export tariffs are some of the major pointers used to forecast the market scenario for individual countries. Also, presence and availability of global brands and their challenges faced due to large or scarce competition from local and domestic brands, impact of sales channels are considered while providing forecast analysis of the country data.

Huge Investment by Automakers for Exosome Therapeutics and New Technology Penetration

Global exosome therapeutic market also provides you with detailed market analysis for every country growth in pharma industry with exosome therapeutic sales, impact of technological development in exosome therapeutic and changes in regulatory scenarios with their support for the exosome therapeutic market. The data is available for historic period 2010 to 2017.

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Exosome therapeutic Market Report- Trends Key Programs Analysis and Competitive Landscape and Forecast 2028 Amite Tangy Digest - Amite Tangy Digest

Trained as a chemist, biophysicist, internist, and cardiologist, Mark Yeager is eager to propel the Frost Institute for Chemistry and Molecular Science into a leading research center.

Even in his youth Mark Yeager could picture the door to his future. Scuffed, chipped, and almost black from layers of varnish, the old, wooden door had a frosted window with five words stenciled in glossy black: Laboratory of Dr. Mark Yeager.

Yet Yeager, the inaugural executive director of the University of Miamis Frost Institute for Chemistry and Molecular Science (FICMS), is quite happy that his new lab in the 94,000-square-foot building slated to open late next year wont even have a door. The $60 million facilitys open floor plan was designed to encourage the free flow of people and ideasand help transform the University into one of the worlds premier research centers for improving the health of humans and that of our planet.

That is the vision, but its not a fantastical vision, said Yeager, a distinguished biophysicist and cardiologist whose top priority is attracting a diverse and elite group of scientists as the institutes first faculty. It is achievable, and it will happen because the University has not wavered in its commitment to elevate STEM (science, technology, engineering, and mathematics) to advance scientific discovery. Theres something going on here thats organic and alive and excitingand Im thrilled to be part of it.

Yeager, whose own groundbreaking research focuses on the molecular causes of heart disease and viral infections, trained as a chemist at Carnegie-Mellon University, as a physician and biophysicist at Yale University and as an internist and cardiologist at Stanford University. He spent two decades at Scripps Research in California, where he established his first independent laboratory, served as the director of research in cardiology, and helped launch the Skaggs Clinical Scholars Program in Translational Research. He has also served as a consultant and scientific and clinical advisor to several biotech companies.

Now he is transitioning to the University from the University of Virginia School of Medicine (UVA), where he chaired the Department of Molecular Biophysics and Biochemistry for nearly a dozen years and helped establish the Sheridan G. Snyder Translational Research Building. At UVA, he also established one of the nations five regional centers for cryo-electron microscopy (cryoEM)the technique he advanced for flash-freezing, imaging, and studying proteins and other macromolecules in their near-natural state.

It is exciting to see the progress being made on the evolution of our Frost Institutes, starting with Data Science and Computing and now the emergence of Chemistry and Molecular Science. We are fortunate to have Mark overseeing our Frost Institute for Chemistry and Molecular Science and working across the entire institutionhis interdisciplinary knowledge and perspective on chemistry are essential for our success, said Jeffrey Duerk, executive vice president for academic affairs and provost. Mark brings a wealth of knowledge and experience to the University of Miami and we are looking forward to his impactful leadership continuing as we move forward.

Yeager said he knew he was making the right career move on his first visit to the University last November. Although the COVID-19 pandemic had curtailed in-person learning and suspended new construction, he heard the unmistakable sound of heavy equipment as he walked past the royal palms and fountain at the end of Memorial Drive, where the five-story FICMS now stands.

I could see an excavation area and heard a cacophony of construction noise where I had a hunch the institute should be, he recalled. That told me that the University was all in. They had made this commitment to fortify STEM and to do transformational science and nothing was going to stop them. In spite of the pandemic, it was all systems go.

The Universitys longtime benefactors, Phillip and Patricia Frost, enabled that commitment in 2017, when they announced their landmark $100 million gift to establish the Frost Institutes for Science and Engineering, now a key initiative of the Roadmap to Our New Centurythe strategic plan guiding the University toward its centennial mark. The umbrella organization for a group of multidisciplinary research centers patterned after the National Institutes of Health and its network of affiliated institutes, the Frost Institutes were envisioned to translate interdisciplinary research into solutions for real-world problems.

Though Yeager officially started his new role on June 1, he has been heavily involved in planning the FICMS' interior for months. He recently placed a $20 million order to equip the facility with five different electron microscopy instruments that chemists, molecular scientists, and engineers will use to explore the molecular structure of exquisitely beam-sensitive soft materials like proteins, hard materials such as metal alloys, as well as nanomaterials comprised of soft and hard components. Along with the buildings state-of-the-art technology and the Universitys research infrastructure, hes confident its location in the heart of the Coral Gables campus will help him recruit a diverse and elite group of scientists who are exploring challenging avenues of impactful researchsomething he has been driven to do almost his entire life.

An occasional songwriter, guitar player, and jogger who in his younger days ran 18 marathons, Yeager was always fascinated by scientific discoveries that illuminated unknown and unseen worlds. A child of the Sputnik era who began entering science fairs in junior high, he began forging his own career as a physician-scientist while in high school in Colorado Springs, Colorado, where his father, an agricultural economist, settled his family after a number of job-related moves.

Inspired by an experiment in Scientific American magazine, he convinced physicians in the therapeutic radiology department at Penrose Hospital to irradiate his fruit flies so he could compare the effects of administering different doses of radiation on their eye pigments. Delivered in Styrofoam cups, his experiments on what is now called dose fractionationand used to reduce tissue damage during cancer treatmentswon him first place in the U.S. Department of Agricultures 1967 International Science Fair and a research stint in an insect toxicology lab in Berkeley, California.

The following summer, when Yeager returned to Penrose Hospital to work as an orderly, he realized that he loved patient care as much as laboratory research and began plotting how he could pursue both careers.

I just got incredible satisfaction from helping patients get out of bed and into a wheelchair, transfer to a gurney, learn to use crutches, recalled Yeager, who joins the University as one of its 100 Talents for 100 Years, a Roadmap initiative to add 100 new endowed chairs to the faculty by the Universitys 2025 centennial. But I also loved chemistry. I loved physics. I loved too many things.

After earning his undergraduate degree in chemistry from Carnegie-Mellon, he was accepted to the Medical Scientist Training Program at Yale University, where, along with his medical degree, he earned his masters degree and doctorate in molecular biophysics and biochemistry. There, he encountered the first of many trailblazing scientists, including two future Nobel laureates, who would influence his lifes work. His Ph.D. advisor, Lubert Stryer, was particularly influential. Stryer authored a premier textbook of biochemistry, pioneered fluorescence-based techniques to explore the motions of biological macromolecules, and made fundamental discoveries on the molecular basis of vision. Yeagers graduate work on rhodopsin, a photoreceptor membrane protein, triggered his fascination with elucidating the molecular bases for such diseases as sudden cardiac death, heart attacks, HIV-1, and other viral infections.

Yeager completed his medical residency and specialized fellowship training in cardiovascular medicine at Stanford University Medical Center, where he managed the pre- and post-operative care of heart transplant patients and wrote 13 chapters in the book Handbook of Difficult Diagnoses.

He also continued exploring cellular biology in the laboratory of Nigel Unwin, who had collaborated with future Nobel laureate Richard Henderson to pioneer the use of cryoEM to determine the molecular structure of membrane proteinsand inspired Yeagers groundbreaking research on gap junction channels. The electrical conduits that connect every cell in the body to its neighbor, gap junction channels play a critical role in maintaining the normal heartbeat.

That research, which Yeager continued at Scripps and at UVA, explained how gap junction channels behave in their normal state, and during an injured state, such as a heart attack. His quest to answer another question particularly relevant todayhow viruses enter host cells, replicate, and assemble infectious particlesis exemplified by his breakthrough research on the assembly, structure, and maturation of HIV-1, the virus that causes AIDS.

Today, those insights, which Yeager humbly calls a few bricks in the edifice of science, hold important clues for developing new, more effective therapies to prevent HIV-1 infection, repair injured tissue, and treat cancer and cardiovascular diseasethe kind of impactful research that the FICMS was designed to advance with collaborative partners across the University, and beyond.

As a pioneer in the field of cryo-transmission electron microscopy, a forefront technology in materials and biological research, Marks expertise and knowledge will position the University as aleader in these cutting-edge fields, said Leonidas Bachas, dean of the College of Arts and Sciences who served as the initial interim director of the FICMS. We look forward to having him lead the Frost Institute for Chemistry and Molecular Science as we continue to advance the sciences, innovate, and expand research collaborations with our faculty and industry partners.

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Distinguished physician-scientist takes the helm of first Frost Institute - University of Miami

Reparative stem cells have the capability to restore function to damaged tissue by renewing cell growth (shown in green) in cardiac cells destroyed by heart disease.

Approximately 28 million Americans have been diagnosed with heart disease. Traditional medical therapies are not able to fully address the burden of disease, and the shortage of organs for transplantation remains a key barrier more than 117,000 people are on the national transplant list.

This unmet need drives Mayo Clinic researchers to make new discoveries to accelerate regenerative solutions into clinical trials and rapidly provide new hope to patients who can't currently be treated.

Cardiac regeneration is a broad effort that aims to repair irreversibly damaged heart tissue with cutting-edge science, including stem cell and cell-free therapy. Reparative tools have been engineered to restore damaged heart tissue and function using the body's natural ability to regenerate. Working together, patients and providers are finding regenerative solutions that restore, renew and recycle patients' own reparative capacity. Through the vision and generous support of Russ and Kathy Van Cleve, strong efforts are underway to develop discoveries that will have a global impact on ischemic heart disease.

Mayo Clinic researchers are leading efforts in translating new knowledge into applicable therapeutics through a multidisciplinary community of practice. As technology evolves, it offers the potential to regenerate cardiac tissue from noncardiac sources and ultimately provide personalized products and services to people with cardiovascular disease.

The overarching vision for the cardiac regeneration program at Mayo Clinic is to develop new therapies to cure ischemic heart disease. Mayo researchers are developing products for clinical testing that span the disease spectrum, including the following areas:

More information about cardiac regenerative medicine research at Mayo Clinic is on the Van Cleve Cardiac Regenerative Medicine Program website.

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Cardiac Regeneration - Center for Regenerative Medicine ...

This Autologous Stem Cell Based Therapies market report provides vital info on survey data and the present market place situation of each sector. The purview of this Autologous Stem Cell Based Therapies market report is also expected to involve detailed pricing, profits, main market players, and trading price for a specific business district, along with the market constraints. This anticipated market research will benefit enterprises in making better judgments.

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This type of comprehensive and specialized market investigation also ponders the effect of these modernizations on the markets future development. Several innovative businesses are bouncing up in the business that are executing original innovations, unique approaches, and forthcoming contracts in order to govern the worldwide market and build their footprint. It is clear that market participants are making progress to combine the most cutting-edge technology in order to stay competitive. This is achievable since innovative products are introduced into the market on a frequent basis. The range of this Autologous Stem Cell Based Therapies market report extends outside market settings to comprise analogous pricing, gains, vital players, and market value for a major market areas. This foreseeable marketing plan will help firms make more up-to-date decisions.

Key global participants in the Autologous Stem Cell Based Therapies market include:Med cell Europe US STEM CELL, INC. Tigenix Mesoblast Pluristem Therapeutics Inc Brainstorm Cell Therapeutics Regeneus

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Segmentation on the Basis of Application:Neurodegenerative Disorders Autoimmune Diseases Cardiovascular Diseases

Market Segments by TypeEmbryonic Stem Cell Resident Cardiac Stem Cells Umbilical Cord Blood Stem Cells

Table of Content1 Report Overview1.1 Product Definition and Scope1.2 PEST (Political, Economic, Social and Technological) Analysis of Autologous Stem Cell Based Therapies Market2 Market Trends and Competitive Landscape3 Segmentation of Autologous Stem Cell Based Therapies Market by Types4 Segmentation of Autologous Stem Cell Based Therapies Market by End-Users5 Market Analysis by Major Regions6 Product Commodity of Autologous Stem Cell Based Therapies Market in Major Countries7 North America Autologous Stem Cell Based Therapies Landscape Analysis8 Europe Autologous Stem Cell Based Therapies Landscape Analysis9 Asia Pacific Autologous Stem Cell Based Therapies Landscape Analysis10 Latin America, Middle East & Africa Autologous Stem Cell Based Therapies Landscape Analysis 11 Major Players Profile

This market study also includes a geographical analysis of the world market, which includes North America, Europe, Asia Pacific, the Middle East, and Africa, as well as several other important regions that dominate the world market. The Market study highlights some of the most important resources that can assist in achieving high profits in the firm. This Autologous Stem Cell Based Therapies market report also identifies market opportunities, which will aid stakeholders in making investments in the competitive landscape and a few product launches by industry players at the regional, global, and company levels. As numerous successful ways are offered in the study, it becomes possible to expand your firm. By referring to this one-of-a-kind market study, one can achieve business stability. With the help of this Market Research Study, you may achieve crucial positions in the whole market. It does a thorough market analysis for the forecast period of 2021-2027.

Autologous Stem Cell Based Therapies Market Intended Audience: Autologous Stem Cell Based Therapies manufacturers Autologous Stem Cell Based Therapies traders, distributors, and suppliers Autologous Stem Cell Based Therapies industry associations Product managers, Autologous Stem Cell Based Therapies industry administrator, C-level executives of the industries Market Research and consulting firms

This comprehensive Autologous Stem Cell Based Therapies market report offers a practical perspective to the current market situation. It also compiles pertinent data that will undoubtedly aid readers in comprehending particular aspects and their interactions in the current market environment. The material offered in this Market research report is discussed in detail on numerous levels, including technological advancements, effective methods, and market penetration factors. The reports recommendations are mostly employed by existing industry participants. It provides sufficient statistical data to comprehend its operation. It also outlines the changes that must be made in order for current businesses to grow and adapt to market developments in the future.

About Global Market MonitorGlobal Market Monitor is a professional modern consulting company, engaged in three major business categories such as market research services, business advisory, technology consulting.We always maintain the win-win spirit, reliable quality and the vision of keeping pace with The Times, to help enterprises achieve revenue growth, cost reduction, and efficiency improvement, and significantly avoid operational risks, to achieve lean growth. Global Market Monitor has provided professional market research, investment consulting, and competitive intelligence services to thousands of organizations, including start-ups, government agencies, banks, research institutes, industry associations, consulting firms, and investment firms.ContactGlobal Market MonitorOne Pierrepont Plaza, 300 Cadman Plaza W, Brooklyn,NY 11201, USAName: Rebecca HallPhone: + 1 (347) 467 7721Email: info@globalmarketmonitor.comWeb Site: https://www.globalmarketmonitor.com

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Autologous Stem Cell Based Therapies Market to Eyewitness Huge Growth by 2027 with Covid-19 Impact The Manomet Current - The Manomet Current

The Autologous Stem Cell Based Therapies Market is expected to grow at a CAGR of 8.98% and is poised to reach US$XX Billion by 2027 as compared to US$XX Billion in 2020. The factors leading to this extraordinary growth is attributed to various market dynamics discussed in the report. Our experts have examined the market from a 360 degree perspective thereby producing a report which is definitely going to impact your business decisions.

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The market research report by DECISIVE MARKETS INSIGHTS looks at several important elements that affect the global industrys development. This research includes a concise explanation of all the variables impacting these market participants growth, as well as information about their organizations, business models, marketing strategies, operational activities, technological integrations, and more. The top competitors in the global industry are included in this market analysis. In addition, the study includes mergers and acquisitions that have improved the product portfolios of various companies. The research provides an in-depth examination of several customer journeys that are relevant to the Autologous Stem Cell Based Therapies market and its sectors. It provides a variety of client perspectives on the products and services.

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Key Companies Operating in this Market

Regeneus, Mesoblast, Pluristem Therapeutics Inc, US STEM CELL, INC., Brainstorm Cell Therapeutics, Tigenix, Med cell Europe

Key Highlights of the Autologous Stem Cell Based Therapies Market Report

Market Segments and other perspective have been studied across 360 degree perspective Both Supply and Demand side mapping has been done to understand the market scenario We have used data triangulation to derive the market numbers Our data and analysis have been verified through C-level Executives while conducting primary interviews Porters Five Forces Analysis, Swot, Analysis, PEST Analysis, Value Chain Analysis and Market Attractiveness would be an added advantage in the report Market Size is Provided from 2019 to 2027; whereas CAGR is Provided from 2020 to 2027 Historical Year: 2019; Base Year: 2020; Forecast Years: 2020 2027

Market Segmentation and Scope of the Global Autologous Stem Cell Based Therapies Market

Market by TypeEmbryonic Stem CellResident Cardiac Stem CellsUmbilical Cord Blood Stem Cells

Market by ApplicationNeurodegenerative DisordersAutoimmune DiseasesCardiovascular Diseases

The study digs deeper into their concerns and common issues across a variety of consumer touchpoints. The consultation and business intelligence solutions will assist interested parties, including CXOs, in developing a user experience that is tailored to their specific requirements. This will assist them in their efforts to increase customer engagement with their companies. The area experts conscious attempt to understand how certain industry owners succeed in keeping a competitive edge which makes the research intriguing. A cursory look at the true competitors adds a lot to the entire studys appeal. Possibilities that assist commodity owners in determining the size of their business offer value to the overall study. Furthermore, the reports research study informs readers about core COVID-19 issues and possible remedies.

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What are the greatest investment options for expanding into new product and service categories? What value propositions should companies aim for when investing in new research & innovation? Which legislation will assist stakeholders to improve their supply chain network the most? Which regions could see consumption in particular segments mature shortly? What are some of the greatest vendor cost management tactics that some well-established players have found to be successful?

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Autologous Stem Cell Based Therapies Market 2021 Industry Statistics, Applications, Forecast 2026, and Key Player Analysis- Regeneus, Mesoblast,...

The treatment of patients with newly diagnosed multiple myeloma is an evolving area, said Pianko. The drug combinations we have now are highly effective, but many of the options coming [down the pike] could allow us to provide deeper responses for patients. Data supporting the use of quadruplet regimens for [this patient population] are also coming.

Future trials will help us [determine] which of the triplet backbones will be the best partner for a CD38-based quadruplet regimen. However, before quadruplets can really be considered a true new standard of care, more data are required, added Pianko, a clinical assistant professor at the University of Michigan Health.

During the 2021 Institutional Perspectives in Cancer webinar on multiple myeloma, faculty from the University of Michigan Health zeroed in on therapeutic updates in the frontline and relapsed settings and how more novel approaches, including CAR T-cell therapy, are shifting best practices in the paradigm. Pianko, who chaired the event, noted that the webinar had a key role in helping to establish and connect the academic institution with local referring community providers to discuss cutting edge developments in myeloma treatment.

In an interview with OncLive, Pianko reflected on the abovementioned topicsspecifically how he approaches patients with newly diagnosed multiple myeloma, and differentiating options based on transplant eligibility, as well as which emerging immune-based therapies he is most intrigued by.

Pianko: My approach to the treatment of [patients with] newly diagnosed multiple myeloma incorporates a very patient-centric [tactic]. I look at multiple factors specific to the patient, which can help to guide treatment decisions, [including] age, other medical conditions, cardiovascular risk, pre-existing neuropathy, and transplant eligibility. These factors play into how we select treatment.

Recent data from several trials have allowed for multiple choices in the frontline setting that would be appropriate for both transplant-eligible and -ineligible patients with multiple myeloma. Largely, tailoring therapy to a specific patient is becoming more possible with much of the data we have in newly diagnosed multiple myeloma.

For the transplant-eligible population, our current practice is to generally use triplet regimens, [such as] bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone [VRd] or carfilzomib [Kyprolis], lenalidomide, and dexamethasone [KRd]. The patients age, cytogenetic risk, and pre-existing neuropathy can help us to choose [between these triplet regimens].

The ENDURANCE trial [NCT01863550] was a large, randomized, phase 3 study that compared VRd with KRd and showed that VRd was not superior to KRd. The study highlighted that there is a known difference in the adverse effect [AE] profiles of these [triplets]. The patients getting VRd had a high incidence of treatment discontinuation [because of] treatment-related AEs, including peripheral neuropathy, which is associated with bortezomib. In the KRd combination, high incidences of cardiac, pulmonary, and renal toxicities [were observed].

Largely, there [doesnt] seem to be a difference in terms of progression-free survival [PFS] between the 2 groups, but we did see a difference in the AE profiles. The basis for choosing one [triplet] over the other can be guided by the expected AEs and driven by the [individual] patient.

In my practice, I tend to favor KRd in young patients with newly diagnosed multiple myeloma without significant medical comorbidities and independent of cytogenetic risk. [This is] because of the peripheral neuropathy bortezomib [can cause] that can be permanent. For many patients who have a life expectancy of potentially at least 1 decade, the cumulative quality-of-life burden of daily pain from peripheral neuropathy is a significant issue to consider.

My discussion with my patients often discusses the risk of peripheral neuropathy and cardiopulmonary AEs from carfilzomib. Ultimately, after discussing [these risks] with the patient, we together choose which [treatment] is the most appropriate way forward.

In the transplant-ineligible patient population, there are younger patients who have medical comorbidities that might preclude a transplant, and we have our older patients. Generally, [transplant ineligibility] is in the range of 75 to 80 years old. That is when we could classify someone as being potentially transplant ineligible but [we need to consider] geriatric and frailty assessments that can help guide us.

For patients who are intermediate-fit or frail, we might consider a doublet regimen, such as lenalidomide plus dexamethasone [Rd]. The inclusion of daratumumab to this doublet [based on] the MAIA trial [NCT02252172] showed us that [Rd plus daratumumab] is a viable approach for patients with newly diagnosed, transplant-ineligible multiple myeloma. The toxicity profile of daratumumab pairs well [with Rd] in this [patient population] to be [considered] a potential standard of care.

Other regimens include the VRd-lite regimen, which uses a modified dose and schedule for bortezomib and lenalidomide. That is another option for our transplant-ineligible patients.

A study was recently published looking at a modified schedule of lenalidomide/dexamethasone where patients would get [the doublet] for 9 cycles and then were able to de-escalate [treatment] and drop the dexamethasone. It seems like this approach is another viable option for our transplant-ineligible patients, particularly those with intermediate-fit or frail disease.

The take-home message is that there are multiple options that we can choose from in both the transplant-eligible and -ineligible patient populations.

The role of daratumumab in the frontline setting for multiple myeloma is an evolving one. Based on the MAIA trial, Rd plus daratumumab is now an FDA-approved regimen for patients with newly diagnosed, transplant-ineligible multiple myeloma. We have seen promising early data from the GRIFFIN study [NCT02874742], which looked at the quadruplet combination of daratumumab plus VRd vs VRd alone.

We saw [from the GRIFFIN trial] that the addition of daratumumab to this regimen was another viable approach. We saw superior depth of response and higher rates of stringent complete responses in up to 60% of patients [treated with] daratumumab plus VRd vs about 20% for the triplet regimen. We also saw a higher degree of minimal residual disease [MRD]negative disease with the quadruplet [compared with the triplet]. The safety profile [with the quadruplet] was acceptable, and namely, the stem cell collection did not seem to be compromised by the inclusion of daratumumab in the up-front setting. Patients were able to successfully collect stem cells without any compromise in the quadruplet arm.

There is a large, international, phase 3 trial called the Perseus trial [NCT03710603], which is going to further evaluate the quadruplet vs triplet combinations that were evaluated in the GRIFFIN trial. [The results of the Perseus trial] should provide further information as to whether [daratumumab plus VRd] could be a potential standard [treatment for patients with] newly diagnosed multiple myeloma.

The KRd triplet [is also] a potential backbone for daratumumab-based therapy and there have also been some exciting studies looking at that [quadruplet]. At the University of Alabama at Birmingham, the phase 2 MASTER trial [NCT03224507] was led by Luciano J. Costa, MD, and looked at daratumumab plus KRd as a potential approach in newly diagnosed multiple myeloma.

There was also a recently reported small study out of Memorial Sloan Kettering Cancer Center called the MANHATTAN trial, which looked at weekly KRd plus daratumumab. In about 41 patients enrolled in the non-randomized trial, the overall response rate was 100%, and 39 patients had a very good partial response or better. Also, these patients had an exceedingly high rate of MRD-negative disease. This is a promising potential option, but randomized data need to be evaluated [because] this was a small, non-randomized study.

Speaking to that, C. Ola Landgren, MD, of the University of Miami Miller School of Medicine, is leading a multicenter, phase 3 trial called ADVANCE [NCT04268498] thatis looking at VRd vs KRd vs daratumumab plus KRd. It is a 3-arm, randomized trial that is likely to provide further data on the feasibility and efficacy of using [these triplets and quadruplets] in the up-front setting.

[Determining] the standard of care for patients with newly diagnosed multiple myeloma has become complicated these days. There are several trials in progress that can help answer this question soon. However, currently, daratumumab is a promising potential partner for each of our backbone triplets. From my perspective, phase 3 data are required to cement a quadruplet option as a standard of care for newly diagnosed multiple myeloma.

I anticipate that these upcoming trials in progress will show us whether a quadruplet regimen is the way to go for newly diagnosed disease, but those data are not available yet.

The management of toxicities from multi-drug regimens in newly diagnosed myeloma is an important consideration. When looking at combinations that include daratumumab and immunomodulatory drugs, such as lenalidomide, then cytopenias, low blood counts, and low neutrophil counts can certainly be an issue early on in treatment. Dose modifications of lenalidomide and potential use of growth factor support can be helpful in maintaining the blood counts to a sufficient level so that we can continue to give patients the highest doses [of the medications] to achieve deep remissions.

The peripheral neuropathy [associated with] bortezomib requires careful management. Much of the published data from these duties included twice-weekly subcutaneous bortezomib on days 1, 4, 8, and 11 at 1.3 mg/m2. In the community [setting] and in our practice, we use a modified schedule of once-weekly bortezomib that has a much lower rate of peripheral neuropathy.

Much progress [is being done regarding] the treatment of patients with relapsed/refractory multiple myeloma. [We are starting to] use immunotherapeutic drugs to try to harness the power of the immune system to attack myeloma. Myeloma has been such an exciting area of practice with all these new agents that have been coming out for patients with relapsed disease.

There are several drugs in this setting that are exciting and could potentially be considered as options for the newly diagnosed patient population. However, we are still several years away from [those drugs being introduced to the armamentarium].

Data presented during the 2020 ASH Annual Meeting showed that a host of bispecific antibodies targeting BCMA [are being investigated]. BCMA is a receptor protein on the surface of myeloma cells that seems to be universally expressed on myeloma plasma cells. [BCMA] is a good target for immune-based treatments and the advantage of bispecific antibodies is that they are off-the-shelf agents. They clearly offer a way to provide rapid responses [to patients].

Looking ahead, the current challenges of cytokine release syndrome [CRS] and dealing with the toxicities of [cellular therapies] are important to figure out, especially if there is any relationship between CRS and tumor burden. Bringing these agents into the frontline setting with patients who have a much larger tumor burden is going to be something to carefully consider in future trials. Yet, these drugs are not far enough along to be considered for frontline treatment, but they [yield] potent effects and can be administered off-the-shelf to patients.

It will be fascinating to see how the bispecific antibodies are incorporated into frontline treatment, as well as the early-relapse setting, but we are several years away from that. We have yet to see among many competitors in the bispecific antibody race which one will become available first and which will be the best. Will we have multiple options in this category? All these questions have yet to be answered.

CAR T-cell therapy is another platform that has been very exciting. With the recent FDA approval of idecabtagene vicleucel [Abecma], we have another option for heavily relapsed patients. It will be interesting to see if we can use CAR T-cell therapy in earlier lines of therapy and what effects [that would yield].

CAR T-cell therapy does require a fair amount of preparation, planning, manufacturing time, and lead time, so the logistical considerations for administering CAR T-cell therapy are significant. Likely, if [this treatment] is going to be considered in the frontline setting, patients will receive other agents prior as preparation for CAR T-cell therapy.

There is a fascinating future for immunotherapy in myeloma. The years to come will show us whether [bispecific antibodies and CAR T-cell therapies] have a role for the treatment of newly diagnosed disease.

The other thing to consider is treatment with checkpoint inhibitors has had a checkered history in myeloma. PD-1 inhibitors were shown to be toxic in combination with lenalidomide or pomalidomide [Pomalyst]. The checkpoint blockade approach, which has been successful in many other tumor types, has not had a future in myeloma; however, other novel immune checkpoints are being considered in the relapsed setting with TIGIT and LAG3 [inhibitors]. These are agents are being evaluated in ongoing trials.

There are other potential approaches we can use to modulate the immune system for the treatment of patients with multiple myeloma, but it takes many years to do these studies and establish safety and [efficacy]. It will be some time before we have other immune therapies applied to the frontline setting.

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Quadruplets, Immune-Based Regimens Slated to Expand the Frontline Myeloma Paradigm - OncLive

By Sofia MoutinhoMay. 20, 2021 , 11:05 AM

They are no bigger than sesame seeds, and they pulse with a hypnotic rhythm. These are human minihearts, the first to be created in the lab with clearly beating chambers. The miniature organs, or organoids, mimic the working heart of a 25-day-old human embryo and could help unravel many mysteriesincluding why babies hearts dont scar after they experience a heart attack.

This is a great study, says Zhen Ma, a bioengineer who develops heart organoids at Syracuse University and was not part of the new research. The experiment is very important for understanding congenital heart defects and human heart formationwork that has so far relied on animal models, he says.

Although miniorgans like brains, guts, and livers have been grown in dishes for more than 10 years, heart organoids have been more challenging. The first ones, comprised of mouse cardiac cells, could contract rhythmically in a dish, but they looked more like a lump of cardiac cells than a proper heart, says Aitor Aguirre, a stem cell biologist at Michigan State University who has created his own beating human heart organoid, described in a preprint posted to Research Square. An organoid should recapitulate the function of the organ, he says. With a heart, You would expect chambers and pumping, because this is what the heart does.

To create heart organoids whose cells self-organize like those in an embryo, the authors of the new study programmed human pluripotent stem cells, which have the ability to differentiate into any kind of tissue, into various types of cardiac cells. They aimed to create the three tissue layers present in the walls of a heart chamber, one of the first parts of the heart to develop. Next, the researchers immersed the stem cells in different concentrations of growth-promoting nutrients until they found a recipe that coaxed the cells to form tissues in the same order and shape seen in embryos.

After 1 week of development, the organoids are structurally equivalent to the heart of a 25-day-old embryo. At this stage, the heart has only one chamber, which will become the left ventricle of the mature heart. The organoids are about 2 millimeters in diameter and include the main types of cells typically present in this stage of development: cardiomyocytes, epithelial cells, fibroblasts, and epicardium. They also have a clearly defined chamber that beats at 60 to 100 times per minute, the same rate of an embryos heart around the same age, the team reports today in Cell.

When I saw it the first time, I was amazed that these chambers could form on their own, says lead author Sasha Mendjan, a stem cell biologist at the Institute of Molecular Biotechnology at the Austrian Academy of Sciences. The amazing thing is that you see immediately whether the experiment worked and the organoid is functional, since it beatsunlike other organs.

The minihearts, which have so far survived for more than 3 months in the lab, will help scientists see heart development in unprecedented detail. They might also reveal the origins of cardiac problems like congenital heart defects in babies and cardiac cell death after heart attacks, Mendjan says. You cannot fully understand something until you can re-create it, he says, loosely quoting the Nobel physicist Richard Feynman.

Mendjan and his colleagues also froze pieces of the organoids to test their response to injury. They saw that cardiac fibroblasts, a type of cell responsible for maintaining tissue structure, migrated to the damaged areas to repair the dead cells, just as in babies that experience heart attacks. It has long been a mystery why babies hearts can regenerate after such injury without scarring, unlike those of adults. Now, we have a controlled and clean system outside of the human body to easily study this process, Mendjan says.

Aguirre says the next logical step is to connect beating heart organoids to vascular networks and test their ability to pump blood. Mendjans team plans to try to adjust the nutrient broth to produce organoids with all four chambers. With such advanced heart organoids, researchers could explore the many developmental heart problems that arise when these additional cavities start to form.

For Ma, growing a more adultlike heart organoid, with all its chambers and structures, is the future of the field. But he doesnt think this will happen in the next decade. For a complete heartlike organoid, he says, there is still a long way to go.

Continued here:
Lab-grown minihearts beat like the real thing - Science Magazine

DUBLIN, May 21, 2021 /PRNewswire/ -- The "Cell Therapy - Technologies, Markets and Companies" report from Jain PharmaBiotech has been added to ResearchAndMarkets.com's offering.

This report describes and evaluates cell therapy technologies and methods, which have already started to play an important role in the practice of medicine. Hematopoietic stem cell transplantation is replacing the old fashioned bone marrow transplants. The role of cells in drug discovery is also described. Cell therapy is bound to become a part of medical practice.

The cell-based markets was analyzed for 2020, and projected to 2030. The markets are analyzed according to therapeutic categories, technologies and geographical areas. The largest expansion will be in diseases of the central nervous system, cancer and cardiovascular disorders. Skin and soft tissue repair, as well as diabetes mellitus, will be other major markets.

The number of companies involved in cell therapy has increased remarkably during the past few years. More than 500 companies have been identified to be involved in cell therapy and 316 of these are profiled in part II of the report along with tabulation of 306 alliances. Of these companies, 171 are involved in stem cells.

Profiles of 73 academic institutions in the US involved in cell therapy are also included in part II along with their commercial collaborations. The text is supplemented with 67 Tables and 26 Figures. The bibliography contains 1,200 selected references, which are cited in the text.

Stem cells are discussed in detail in one chapter. Some light is thrown on the current controversy of embryonic sources of stem cells and comparison with adult sources. Other sources of stem cells such as the placenta, cord blood and fat removed by liposuction are also discussed. Stem cells can also be genetically modified prior to transplantation.

Cell therapy technologies overlap with those of gene therapy, cancer vaccines, drug delivery, tissue engineering, and regenerative medicine. Pharmaceutical applications of stem cells including those in drug discovery are also described. Various types of cells used, methods of preparation and culture, encapsulation, and genetic engineering of cells are discussed. Sources of cells, both human and animal (xenotransplantation) are discussed. Methods of delivery of cell therapy range from injections to surgical implantation using special devices.

Cell therapy has applications in a large number of disorders. The most important are diseases of the nervous system and cancer which are the topics for separate chapters. Other applications include cardiac disorders (myocardial infarction and heart failure), diabetes mellitus, diseases of bones and joints, genetic disorders, and wounds of the skin and soft tissues.

Regulatory and ethical issues involving cell therapy are important and are discussed. The current political debate on the use of stem cells from embryonic sources (hESCs) is also presented. Safety is an essential consideration of any new therapy and regulations for cell therapy are those for biological preparations.

Key Topics Covered:

Part One: Technologies, Ethics & Regulations

Executive Summary

1. Introduction to Cell Therapy

2. Cell Therapy Technologies

3. Stem Cells

4. Clinical Applications of Cell Therapy

5. Cell Therapy for Cardiovascular Disorders

6. Cell Therapy for Cancer

7. Cell Therapy for Neurological Disorders

8. Ethical, Legal and Political Aspects of Cell therapy

9. Safety and Regulatory Aspects of Cell Therapy

Part II: Markets, Companies & Academic Institutions

10. Markets and Future Prospects for Cell Therapy

11. Companies Involved in Cell Therapy

12. Academic Institutions

13. References

For more information about this report visit https://www.researchandmarkets.com/r/oletip

Media Contact:

Research and Markets Laura Wood, Senior Manager [emailprotected]

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Global Cell Therapy Markets, Technologies, and Competitive Landscape Report 2020-2030: Applications, Cardiovascular Disorders, Cancer, Neurological...

DUBLIN, May 21, 2021 /PRNewswire/ -- The "Cardiovascular Drug Delivery - Technologies, Markets & Companies" report from Jain PharmaBiotech has been added to ResearchAndMarkets.com's offering.

The cardiovascular drug delivery markets are estimated for the years 2018 to 2028 on the basis of epidemiology and total markets for cardiovascular therapeutics.

The estimates take into consideration the anticipated advances and availability of various technologies, particularly drug delivery devices in the future. Markets for drug-eluting stents are calculated separately. The role of drug delivery in developing cardiovascular markets is defined and unmet needs in cardiovascular drug delivery technologies are identified.

Drug delivery to the cardiovascular system is approached at three levels: (1) routes of drug delivery; (2) formulations; and finally (3) applications to various diseases.

Formulations for drug delivery to the cardiovascular system range from controlled release preparations to delivery of proteins and peptides. Cell and gene therapies, including antisense and RNA interference, are described in full chapters as they are the most innovative methods of delivery of therapeutics. Various methods of improving the systemic administration of drugs for cardiovascular disorders are described including the use of nanotechnology.

Cell-selective targeted drug delivery has emerged as one of the most significant areas of biomedical engineering research, to optimize the therapeutic efficacy of a drug by strictly localizing its pharmacological activity to a pathophysiologically relevant tissue system. These concepts have been applied to targeted drug delivery to the cardiovascular system. Devices for drug delivery to the cardiovascular system are also described.

The role of drug delivery in various cardiovascular disorders such as myocardial ischemia, hypertension, and hypercholesterolemia is discussed. Cardioprotection is also discussed. Some of the preparations and technologies are also applicable to peripheral arterial diseases. Controlled release systems are based on chronopharmacology, which deals with the effects of circadian biological rhythms on drug actions. A full chapter is devoted to drug-eluting stents as treatment for restenosis following stenting of coronary arteries.Fifteen companies are involved in drug-eluting stents.

New cell-based therapeutic strategies are being developed in response to the shortcomings of available treatments for heart disease. Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure.

Cell therapy approaches include attempts to reinitiate cardiomyocyte proliferation in the adult, conversion of fibroblasts to contractile myocytes, conversion of bone marrow stem cells into cardiomyocytes, and transplantation of myocytes or other cells into injured myocardium.

Advances in the molecular pathophysiology of cardiovascular diseases have brought gene therapy within the realm of possibility as a novel approach to the treatment of these diseases. It is hoped that gene therapy will be less expensive and affordable because the techniques involved are simpler than those involved in cardiac bypass surgery, heart transplantation and stent implantation.

Gene therapy would be a more physiologic approach to deliver vasoprotective molecules to the site of vascular lesions. Gene therapy is not only a sophisticated method of drug delivery; it may at times need drug delivery devices such as catheters for transfer of genes to various parts of the cardiovascular system.

Selected 83 companies that either develop technologies for drug delivery to the cardiovascular system or products using these technologies are profiled and 80 collaborations between companies are tabulated. The bibliography includes 200 selected references from recent literature on this topic.

Key Markets

Key Topics Covered:

Executive Summary

1. Cardiovascular Diseases

2. Methods for Drug Delivery to the Cardiovascular System

3. Cell Therapy for Cardiovascular Disorders

4. Gene Therapy for Cardiovascular Disorders

5. Drug-Eluting Stents

6. Markets for Cardiovascular Drug Delivery

7. Companies involved in Cardiovascular Drug Delivery

8. References

For more information about this report visit https://www.researchandmarkets.com/r/qqxmpd

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Global Cardiovascular Drug Delivery Markets Report 2021: Cell and Gene Therapies, Including Antisense and RNA Interference are Described in Detail -...

DUBLIN--(BUSINESS WIRE)--The "Cardiovascular Drug Delivery - Technologies, Markets & Companies" report from Jain PharmaBiotech has been added to ResearchAndMarkets.com's offering.

The cardiovascular drug delivery markets are estimated for the years 2018 to 2028 on the basis of epidemiology and total markets for cardiovascular therapeutics.

The estimates take into consideration the anticipated advances and availability of various technologies, particularly drug delivery devices in the future. Markets for drug-eluting stents are calculated separately. The role of drug delivery in developing cardiovascular markets is defined and unmet needs in cardiovascular drug delivery technologies are identified.

Drug delivery to the cardiovascular system is approached at three levels: (1) routes of drug delivery; (2) formulations; and finally (3) applications to various diseases.

Formulations for drug delivery to the cardiovascular system range from controlled release preparations to delivery of proteins and peptides. Cell and gene therapies, including antisense and RNA interference, are described in full chapters as they are the most innovative methods of delivery of therapeutics. Various methods of improving the systemic administration of drugs for cardiovascular disorders are described including the use of nanotechnology.

Cell-selective targeted drug delivery has emerged as one of the most significant areas of biomedical engineering research, to optimize the therapeutic efficacy of a drug by strictly localizing its pharmacological activity to a pathophysiologically relevant tissue system. These concepts have been applied to targeted drug delivery to the cardiovascular system. Devices for drug delivery to the cardiovascular system are also described.

The role of drug delivery in various cardiovascular disorders such as myocardial ischemia, hypertension, and hypercholesterolemia is discussed. Cardioprotection is also discussed. Some of the preparations and technologies are also applicable to peripheral arterial diseases. Controlled release systems are based on chronopharmacology, which deals with the effects of circadian biological rhythms on drug actions. A full chapter is devoted to drug-eluting stents as treatment for restenosis following stenting of coronary arteries.Fifteen companies are involved in drug-eluting stents.

New cell-based therapeutic strategies are being developed in response to the shortcomings of available treatments for heart disease. Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure.

Cell therapy approaches include attempts to reinitiate cardiomyocyte proliferation in the adult, conversion of fibroblasts to contractile myocytes, conversion of bone marrow stem cells into cardiomyocytes, and transplantation of myocytes or other cells into injured myocardium.

Advances in the molecular pathophysiology of cardiovascular diseases have brought gene therapy within the realm of possibility as a novel approach to the treatment of these diseases. It is hoped that gene therapy will be less expensive and affordable because the techniques involved are simpler than those involved in cardiac bypass surgery, heart transplantation and stent implantation.

Gene therapy would be a more physiologic approach to deliver vasoprotective molecules to the site of vascular lesions. Gene therapy is not only a sophisticated method of drug delivery; it may at times need drug delivery devices such as catheters for transfer of genes to various parts of the cardiovascular system.

Selected 83 companies that either develop technologies for drug delivery to the cardiovascular system or products using these technologies are profiled and 80 collaborations between companies are tabulated. The bibliography includes 200 selected references from recent literature on this topic.

Key Markets

Key Topics Covered:

Executive Summary

1. Cardiovascular Diseases

2. Methods for Drug Delivery to the Cardiovascular System

3. Cell Therapy for Cardiovascular Disorders

4. Gene Therapy for Cardiovascular Disorders

5. Drug-Eluting Stents

6. Markets for Cardiovascular Drug Delivery

7. Companies involved in Cardiovascular Drug Delivery

8. References

For more information about this report visit https://www.researchandmarkets.com/r/p5l8t6

Follow this link:
Global Cardiovascular Drug Delivery Markets Report 2021: Diseases, Methods, Cell Therapy, Gene Therapy, Drug-eluting Stents, Key Markets -...

Myocardial revascularization is an alternate procedure for patients suffering from ischemic heart disease and who cannot undergo interventions like heart bypass surgery due to widespread coronary artery disease, procedure failure, small coronary arteries, or cardiac stenosis. Further, reparative stem cells can restore the function of damaged tissue by renewing cell growth in cardiac cells destroyed by heart disease.

(**Note: The sample of this report is updated with COVID-19 impact analysis**)

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Report Introduction, Overview, and In-depth industry analysis

NOTE: Our analysts monitoring the situation across the globe explains that the market will generate remunerative prospects for producers post the COVID-19 crisis. The report aims to provide an additional illustration of the latest scenario, economic slowdown, and COVID-19 impact on the overall industry.

The report is a combination of qualitative and quantitative analysis of the Myocardial Revascularization, Repair, And Regeneration Products And Therapies Market industry. The global market majorly considers five major regions, namely, North America, Europe, Asia-Pacific (APAC), Middle East and Africa (MEA) and South & Central America (SACM). The report also focuses on the exhaustive PEST analysis and extensive market dynamics during the forecast period.

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Myocardial Revascularization, Repair, And Regeneration Products And Therapies Market Business Strategy and Forecast to 2028 Top Companies Abbott...

Introduction

Although novel drugs have successfully entered the clinical arena of heart failure with reduced ejection fraction (HFrEF), such as the PARADIGM-HF-derived angiotensin receptor neprilysin inhibitor (ARNI), disease-modifying therapies with a prognostic impact for patients affected by heart failure with preserved ejection fraction (HFpEF) are still lacking.15 HF is a complex and highly prevalent syndrome for which the heart undergoes a substantial structural remodeling in patients at risk for major cardiovascular diseases (CVDs) (Figure 1).16 Geneenvironment interactions can be mediated by specific patterns of epigenetic-sensitive changes (mainly DNA methylation and histone modifications) which may modulate the individual responsiveness to HF development.614 This complex molecular circuit seems to trigger early cardiomyocyte loss, cardiac-remodeling, and micro- and macrovascular damage contributing to the development of major CVDs which may lead to differential HF clinical phenotypes.614 Of note, the reversible nature of epigenetic-sensitive changes has been translated in the clinical management of specific hematological malignancies with the approval by the Food and Drug Administration (FDA) of some epidrugs, such as decitabine (Dacogen) and azacitidine (Vidaza), as DNA methylation inhibitors, as well as vorinostat (Zolinza), belinostat (Beleodaq), romidepsin (Istodax), and panobinostat (Farydak), as histone deacetylase inhibitors (HDACi).15 Epidrugs are now providing a novel vision for personalized therapy of HF and heart transplantation, opening up novel options for management of the affected patients.1518 At molecular level, we can classify the epidrugs in: direct epidrugs [eg, the bromodomain and extra-terminal (BET) protein inhibitor apabetalone]; and repurposed drugs with potential, indirect (non-classical) epigenetic-oriented interference by which they may exert cardioprotective functions [eg, hydralazine, metformin, statins, and sodium-glucose co-transporter-2 inhibitors (SGLT2i)] or nutraceutical compounds [eg, omega-3 polyunsaturated fatty acids (PUFAs)]. Encouraging results are coming from large randomized trials evaluating the putative beneficial effects of combining epidrugs with the conventional therapy in patients with HF.1422 Our goal is to update on the emerging epigenetic-based strategies which may be useful in the prevention and treatment of HFrEF and HFpEF (Figure 1).

Figure 1 The possible role of epitherapy in the current framework of HFrEF and HFpEF management. The unstable transition state from the ACC/AHA Stage A/B to Stage C/D-Acute/Hospitalized HF is the key point in the treatment of HFrEF and HFpEF. The epitherapy, mainly apabetalone, statins, metformin, SGLT2i, and PUFAs in addition to the standard of the care may improve personalized therapy of affected patients.

Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; SGLT2i, sodium glucose co-transporter 2 inhibitors; PUFAs, polyunsaturated fatty acids.

The bromodomain and extra terminal domain (BET) proteins, including the ubiquitous BRD2, BRD3, BRD4, and the testis-restricted BRDT, are epigenetic readers (via bromodomains) existing in the form of nuclear multidomain docking platforms which control the cell-specific activation of gene expression profiles.23 Experimental data demonstrated that BETs regulate vascular cells, cardiac myocytes, and inflammatory cells,24 and their activity may be extended to the regulation of calcification, thrombosis, as well as lipid and lipoprotein metabolism, all of which participate in atherogenesis.2527 In particular, BRD4 facilitated the expression of multiple proinflammatory and proatherosclerotic targets involved in thrombosis, leukocyte adhesion, and endothelial barrier function, thus identifying BRD4 as a possible therapeutic target in CVD setting.24 The quinazolone (RVX-208), known as apabetalone, is a derivative of the plant polyphenol resveratrol. Apabetalone acts as a direct epidrug by selectively targeting the BET family member BRD4 to block its interaction with acetylated lysines located in histones.28 Apabetalone-BRD4 binding can impact cholesterol levels and inflammation; in fact, apabetalone stimulates ApoA-I gene expression and increases high-density lipoprotein (HDL).29,30 Besides, apabetalone may attenuate the development of cardiac hypertrophy31 and cardiac fibrosis,32 suggesting novel options for the management of HF.

Resverlogix developed apabetalone (RVX-208), a first-in-class, orally available, small molecule for the treatment of atherosclerosis and associated CVDs.20 BETonMACE (NCT02586155) is the first Phase 3 clinical trial evaluating the cardiovascular efficacy and safety of apabetalone.22 Recent results from the BETonMACE study have demonstrated that apabetalone is associated with a reduction in first HF hospitalization and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome as compared to controls (placebo-treated patients).22 Additionally, a significant increase in HDL and a decrease in alkaline phosphatase levels have been observed following 24 weeks of apabetalone treatment as compared to the placebo group.22 However, investigators were unable to make a distinction between HF in the setting of preserved or reduced ejection fraction. Thus, further clinical trials should be designed to evaluate the putative beneficial effects of apabetalone in HFrEF and HFpEF, separately.

Preclinical studies demonstrated that pharmacological HDACi,3336 BET inhibitors,31,37 and DNA methylation inhibitors38 can attenuate cardiac remodeling (cardiomyocyte hypertrophy and fibrosis). Although not originally developed as epidrugs, hydralazine (anti-hypertensive drug), metformin, and SGLT2i (anti-diabetic drugs), statins (anti-dyslipidemic drugs), and PUFAs (nutraceuticals) might have downstream epigenetic-oriented effects in cardiac cells. Hydralazine, for example, lowers blood pressure by a direct relaxation of vascular smooth muscle; additionally, it may reduce DNA methylation and improve cardiac function through increasing sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and modulating calcium homeostasis in cardiomyocytes.39 Statins are used as a first-line treatment to decrease serum cholesterol levels in dyslipidemic patients and as primary and secondary prophylaxis against atherosclerosis and associated CVDs.6 Many of their non-classical pleiotropic properties relevant for endothelial health are mediated by epigenetic mechanisms which improve blood flow, decrease LDL oxidation, enhance atherosclerotic plaque stability and decrease proliferation of vascular smooth muscle cells and platelet aggregation.6 Metformin is a first-line drug in the treatment of overweight and obese type 2 diabetic patients.10 Mechanistically, metformin may also have epigenetic-oriented effects through activating the AMP-activated protein kinase (AMPK) which, in turn, can phosphorylate and inhibit epigenetic enzymes such as histone acetyltransferases (HATs), class II HDAC, and DNA methyltransferases (DNMTs).40 Both metformin41,42 and statins43,44 may reduce cardiac fibrosis; however, whether their beneficial effects are mediated by epigenetic-oriented responses has yet to be demonstrated. Furthermore, SGLT2i are a new group of oral drugs used for treating type 2 diabetes and its cardiovascular/renal complications.45 Animal models have demonstrated that empagliflozin46,47 and dapagliflozin48 may improve hemodynamics in HF by increasing renal protection and cardiac fibrosis. Interestingly, inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by empagliflozin;49 this observation has provided insights about mechanisms by which SGLT2i can reduce cardiovascular mortality in man (EMPA-REG trial).50

An effective therapy for HFpEF has yet to be established. Hydralazine is frequently used in HFrEF, and represents a potential DNA methylation inhibitor.39 DNA methylation is the most studied direct epigenetic change with potential clinical implications in major CVDs and the development of HF.7,14 This epigenetic signature mainly involves methylation of CpG islands in the gene promoters leading to a specific long-term silencing of gene expression.7,14 A completed Phase 2 clinical trial (NCT01516346) evaluated the effect of prolonged therapy (24 weeks) with isosorbide dinitrate (ISDN) hydralazine on arterial wave reflections (primary endpoint) as well as left ventricular (LV) mass, fibrosis and diastolic function, and exercise capacity (6-minute walk test) in patients with HFpEF, New York Heart Association (NYHA) Class IIIV symptoms, and standard therapy as defined by ACEi, ARB, beta-blockers, or calcium channel blockers (CCBs).51 Results from this trial reported that ISDN, with or without hydralazine, had deleterious effects on reflection magnitude, LV remodeling, or submaximal exercise thus not supporting their routine use in patients with HFpEF.51

Metformin has been associated with a reduced mortality in patients with HFpEF, even if female gender was associated with worse outcomes.52 Recently, it has been observed that a long-term treatment with metformin can improve LV diastolic function and hypertrophy, decrease the incidence of new-onset HFpEF, and delay disease progression in patients with type 2 diabetes and hypertension.53 Besides, a prospective phase 2 clinical trial (NCT03629340) is testing the therapeutic efficacy of metformin in patients with pulmonary hypertension and HFpEF by evaluating exercise hemodynamics, functional capacity, skeletal muscle signaling, and insulin sensitivity. However, results have not been published. A recent study based on the JASPER registry, a multicenter, observational, prospective cohort of Japanese patients aged 20 years requiring hospitalization for acute HFpEF has reported that the use of statins could reduce mortality in affected patients without coronary heart disease.54 Furthermore, the use of statins was associated with improved clinical outcomes in patients with HFpEF but not in patients with HFrEF (or mid-range ejection fraction).55 A reduced rate of major adverse cardiac events, cardiovascular death and all-cause mortality was associated with SGLT2i treatment in both HFpEF and HFrEF patients as compared to placebo.56,57 However, the observed cardiovascular and renal benefits cannot be fully explained by improvement in risk factors (such as glycemia, blood pressure or dyslipidemias) suggesting that other molecular mechanisms may explain the cardiovascular benefits.56 Interestingly, the SGLT2i-related epigenetic interference may arise from their ability to increase the circulating and tissue levels of -hydroxybutyrate, a specific molecule able to generate a pattern of histone modifications (known as -hydroxybutyrylation) which are associated with the beneficial effects of fasting.58 Besides, the DELIVER (NCT03619213) multicenter, randomized, double-blind, placebo-controlled study of 6263 HFpEF patients will evaluate the effect of dapagliflozin 10 mg (1 per day) as compared to placebo in addition to the standard of care in order to reduce the composite of cardiovascular death or HF events. However, results have not yet been published.

The use of metformin has been generally considered a contraindication in HFrEF patients owing the potential risk of lactic acidosis; however, recent evidence has reported that metformin can provide beneficial effects in reducing the risk of incident HF and mortality in diabetic patients.5961 A completed, observational clinical trial (NCT03546062) has recently performed the evaluation of seriated cardiac biopsies from healthy implanted hearts in type 2 diabetes recipients during 12-month follow-up upon heart transplantation.21 Even if the intra-cardiomyocyte lipid accumulation in type 2 diabetes recipients may start in the early stages after heart transplantation, metformin therapy could reduce lipid accumulation independently of immunosuppressive therapy.21 The DANHEART trial (NCT03514108), a multicenter, randomized, double-blind, placebo-controlled study in 1500 patients with HFrEF will evaluate: 1) whether hydralazine-isosorbide dinitrate as compared to placebo may reduce the incidence of death and HF hospitalization, and 2) if metformin as compared to placebo may reduce the incidence of death, worsening of HF, acute myocardial infarction, and stroke in patients with diabetes or prediabetes. Two large randomized trials demonstrated that statins did not have beneficial effects in management of patients with HFrEF.62,63 Specifically, the CORONA phase 3 trial randomized more than 5000 patients with ischemic HFrEF to rosuvastatin as compared to placebo resulting in no benefits on the primary endpoints, as death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke.62 According to CORONA trial, the GISSI-HF study randomized almost 5000 patients with clinically apparent HF of any cause to rosuvastatin as compared to placebo and observed no benefits on the primary endpoints, as all-cause death or cardiovascular hospitalization.63 However, it is needed to highlight that both trials demonstrated that statins are safe in HF patients. In contrast with the previous evidence, the trial based on the Swedish Heart Failure Registry (21,864 patients with HFrEF, of whom 10,345 were treated with statins) reported an association between the use of statins and improved outcomes, as all-cause mortality, cardiovascular mortality, HF hospitalization, and combined all-cause mortality or cardiovascular hospitalization, especially in patients with ischemic HF.64 Thus, further randomized controlled trials focused on ischemic HF may be warranted. Omega-3 polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are key players in modulating inflammatory process by limiting leucocyte chemotaxis, adhesion molecule expression, leucocyte-endothelium interaction as well as T cell reactivity.65 EPA and DHA are mainly gained from marine food consumption and large population-based studies have shown that Mediterranean diet with PUFA supplementation may aid to prevent CVDs owing to their ability in promoting the release of nitric oxide from endothelial cells and decreasing serum levels of triglycerides.66 Recent evidence has indicated that PUFAs can significantly affect the cellular epigenome mainly thought DNA methylation-sensitive mechanisms.67,68 The GISSI multicenter, double-blind trial enrolled 6975 HF patients (New York Heart Association class IIIV, irrespective of cause and LV ejection fraction) and randomized them to low dose (0.84 g per day) of PUFAs as compared to placebo. PUFAs supplementation reduced risk for total mortality and HF hospitalization when added to standard therapy.19 Furthermore, in the OMEGA-REMODEL trial, high-dose of PUFAs (3.4 g per day) for 6 months post-myocardial infarction reduced infarct size and non-infarct myocardial fibrosis as well as improved ventricular systolic function.69 Taken together, these results suggest that PUFAs may aid to prevent HFrEF. More recently, the MESA longitudinal trial including 6562 participants 45 to 84 years has demonstrated that higher plasma levels of EPA were significantly associated with reduced risk both in HFpEF and HFrEF.70

Although the possibility of improving the HF standard of care with epidrugs is still in its infancy, the BETonMACE study has provided promising results about the use of apabetalone in reducing hospitalization and cardiovascular death. Preclinical models of cardiac remodeling demonstrated that metformin, statins, SGLT2i, and PUFAs4148 can improve vascular health and cardiac fibrosis by modulating specific molecular pathways, and, in part, through downstream epigenetic interference, especially for hydralazine39 and empagliflozin (Figure 2).49 Of note, metformin and SGLT2i can impact on the epigenetic memory phenomenon. This latter suggests that an early glycemia normalization can arrest hyperglycemia-induced epigenetic processes associated with enhanced oxidative stress and glycation of cellular proteins and lipids.71,72 In parallel, an increasing number of clinical trials is evaluating the putative beneficial repurposing of metformin, statins, SGLT2i, and PUFAs in patients with HFpEF and/or HFrEF;19,6264,69,7375 however, despite experimental evidence, none of these trials evaluated their potential epigenetic effects involved in improving the cardiac function. This gap should be overcome to improve personalized therapy of patients with HF. Thus, further randomized trials are needed to clarify whether apabetalone, as well as non-canonical repurposed epidrugs, will really be able to save failing hearts in different HF clinical phenotypes or prevent irreversible damages in high-risk patients. In this context, Network Medicine approaches may help to evaluate a possible repurposing of epidrugs in patients with major CVDs.15,76,77

Figure 2 Direct and indirect epigenetic drugs in preclinical models of HF. Cardiac remodeling includes different pathological phenotypes and each type of drug can selectively improve inflammation, cardiac fibrosis and hypertrophy, calcium homeostasis, and lipid metabolism.

Abbreviations: HF, heart failure; SGLT2i, sodium glucose co-transporter 2 inhibitors.

This work was supported by PRIN2017F8ZB89 from Italian Ministry of University and Research (MIUR) (PI Prof Napoli) and Ricerca Corrente (RC) 2019 from Italian Ministry of Health (PI Prof. Napoli).

The authors report no conflicts of interest in this work.

1. Gronda E, Sacchi S, Benincasa G, et al. Unresolved issues in left ventricular postischemic remodeling and progression to heart failure. J Cardiovasc Med (Hagerstown). 2019;20:640649. doi:10.2459/JCM.0000000000000834.

2. Gronda E, Vanoli E, Sacchi S, et al. Risk of heart failure progression in patients with reduced ejection fraction: mechanisms and therapeutic options. Heart Fail Rev. 2020;25(2):295303. doi:10.1007/s10741-019-09823-z

3. Sokos GG, Raina A. Understanding the early mortality benefit observed in the PARADIGM-HF trial: considerations for the management of heart failure with sacubitril/valsartan. Vasc Health Risk Manag. 2020;16:4151. doi:10.2147/VHRM.S197291

4. Cacciatore F, Amarelli C, Maiello C, et al. Sacubitril/valsartan in patients listed for heart transplantation: effect on physical frailty. ESC Heart Fail. 2020;7:757762. doi:10.1002/ehf2.12610.

5. Clark KAA, Velazquez EJ. Heart failure with preserved ejection fraction: time for a reset. JAMA. 2020;324:15061508. doi:10.1001/jama.2020.15566.

6. Schiano C, Benincasa G, Franzese M, et al. Epigenetic-sensitive pathways in personalized therapy of major cardiovascular diseases. Pharmacol Ther. 2020;210:107514. doi:10.1016/j.pharmthera.2020.107514.

7. Schiano C, Benincasa G, Infante T, et al. Integrated analysis of DNA methylation profile of HLA-G gene and imaging in coronary heart disease: pilot study. PLoS One. 2020;15:e0236951. doi:10.1371/journal.pone.0236951.

8. Benincasa G, Cuomo O, Vasco M, et al. Epigenetic-sensitive challenges of cardiohepatic interactions: clinical and therapeutic implications in heart failure patients. Eur J Gastroenterol Hepatol. 2020. doi:10.1097/MEG.0000000000001867.

9. Benincasa G, Franzese M, Schiano C, et al. DNA methylation profiling of CD04+/CD08+ T cells reveals pathogenic mechanisms in increasing hyperglycemia: PIRAMIDE pilot study. Ann Med Surg (Lond). 2020;60:218226. doi:10.1016/j.amsu.2020.10.016.

10. Napoli C, Benincasa G, Schiano C, et al. Differential epigenetic factors in the prediction of cardiovascular risk in diabetic patients. Eur Heart J Cardiovasc Pharmacother. 2020;6:239247. doi:10.1093/ehjcvp/pvz062.

11. Napoli C, Coscioni E, de Nigris F, et al. Emergent expansion of clinical epigenetics in patients with cardiovascular diseases. Curr Opin Cardiol. 2021;36(3):295300. doi:10.1097/HCO.0000000000000843.

12. Infante T, Forte E, Schiano C, et al. Evidence of association of circulating epigenetic-sensitive biomarkers with suspected coronary heart disease evaluated by Cardiac Computed Tomography. PLoS One. 2019;14:e0210909. doi:10.1371/journal.pone.0210909.

13. de Nigris F, Cacciatore F, Mancini FP, et al. Epigenetic hallmarks of fetal early atherosclerotic lesions in humans. JAMA Cardiol. 2018;3:11841191. doi:10.1001/jamacardio.2018.3546.

14. Napoli C, Benincasa G, Donatelli F, et al. Precision medicine in distinct heart failure phenotypes: focus on clinical epigenetics. Am Heart J. 2020;224:113128. doi:10.1016/j.ahj.2020.03.007.

15. Sarno F, Benincasa G, List M, et al. Clinical epigenetics settings for cancer and cardiovascular diseases: real-life applications of network medicine at the bedside. Clin Epigenetics. 2021;13:66. doi:10.1186/s13148-021-01047-z.

16. Grimaldi V, Vietri MT, Schiano C, et al. Epigenetic reprogramming in atherosclerosis. Curr Atheroscler Rep. 2014;17:476. doi:10.1007/s11883-014-0476-3.

17. Sabia C, Picascia A, Grimaldi V, et al. The epigenetic promise to improve prognosis of heart failure and heart transplantation. Transplant Rev (Orlando). 2017;31:249256. doi:10.1016/j.trre.2017.08.004.

18. Vasco M, Benincasa G, Fiorito C, et al. Clinical epigenetics and acute/chronic rejection in solid organ transplantation: an update. Transplant Rev (Orlando). 2021;35:100609. doi:10.1016/j.trre.2021.100609.

19. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:12231230. doi:10.1016/S0140-6736(08)61239-8.

20. Ray KK, Nicholls SJ, Buhr KA, et al. Effect of apabetalone added to standard therapy on major adverse cardiovascular events in patients with recent acute coronary syndrome and type 2 diabetes: a randomized clinical trial. JAMA. 2020;323:15651573. doi:10.1001/jama.2020.3308.

21. Marfella R, Amarelli C, Cacciatore F, et al. Lipid accumulation in hearts transplanted from nondiabetic donors to diabetic recipients. J Am Coll Cardiol. 2020;75:12491262. doi:10.1016/j.jacc.2020.01.018.

22. Nicholls SJ, Schwartz GG, Buhr KA, et al. Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study. Cardiovasc Diabetol. 2021;20:13. doi:10.1186/s12933-020-01199-x.

23. Gaucher J, Boussouar F, Montellier E, et al. Bromodomain-dependent stage-specific male genome programming by Brdt. EMBO J. 2012;31:38093820. doi:10.1038/emboj.2012.233.

24. Borck PC, Guo LW, Plutzky J. BET epigenetic reader proteins in cardiovascular transcriptional programs. Circ Res. 2020;126:11901208. doi:10.1161/CIRCRESAHA.120.315929.

25. Tonini C, Colardo M, Colella B, et al. Inhibition of bromodomain and extraterminal domain (BET) proteins by JQ1 unravels a novel epigenetic modulation to control lipid homeostasis. Int J Mol Sci. 2020;21:1297. doi:10.3390/ijms21041297.

26. Nicodeme E, Jeffrey KL, Schaefer U, et al. Suppression of inflammation by a synthetic histone mimic. Nature. 2010;468:11191123. doi:10.1038/nature09589.

27. Dey A, Yang W, Gegonne A, et al. BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses. EMBO J. 2019;38:e100293. doi:10.15252/embj.2018100293.

28. Picaud S, Wells C, Felletar I, et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc Natl Acad Sci U S A. 2013;110:1975419759. doi:10.1073/pnas.1310658110.

29. McLure KG, Gesner EM, Tsujikawa L, et al. RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS One. 2013;8:e83190. doi:10.1371/journal.pone.0083190.

30. Bailey D, Jahagirdar R, Gordon A, et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol. 2010;55:25802589. doi:10.1016/j.jacc.2010.02.035.

31. Anand P, Brown JD, Lin CY, et al. BET bromodomains mediate transcriptional pause release in heart failure. Cell. 2013;154:569582. doi:10.1016/j.cell.2013.07.013.

32. Song S, Liu L, Yu Y, et al. Inhibition of BRD4 attenuates transverse aortic constriction- and TGF--induced endothelial-mesenchymal transition and cardiac fibrosis. J Mol Cell Cardiol. 2019;127:8396. doi:10.1016/j.yjmcc.2018.12.002.

33. Ooi JY, Tuano NK, Rafehi H, et al. HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes. Epigenetics. 2015;10:418430. doi:10.1080/15592294.2015.1024406.

34. Ferguson BS, McKinsey TA. Non-sirtuin histone deacetylases in the control of cardiac aging. J Mol Cell Cardiol. 2015;83:1420. doi:10.1016/j.yjmcc.2015.03.010.

35. Chen Y, Du J, Zhao YT, et al. Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice. Cardiovasc Diabetol. 2015;14:99. doi:10.1186/s12933-015-0262-8.

36. Zhang CL, McKinsey TA, Chang S, et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell. 2002;110(4):479488. doi:10.1016/s0092-8674(02)00861-9

37. Spiltoir JI, Stratton MS, Cavasin MA, et al. BET acetyl-lysine binding proteins control pathological cardiac hypertrophy. J Mol Cell Cardiol. 2013;63:175179. doi:10.1016/j.yjmcc.2013.07.017.

38. Russell-Hallinan A, Neary R, Watson CJ, et al. Repurposing from oncology to cardiology: low-dose 5-azacytidine attenuates pathological cardiac remodeling in response to pressure overload injury. J Cardiovasc Pharmacol Ther. 2020:107424842097923. doi:10.1177/1074248420979235

39. Kao YH, Cheng CC, Chen YC, et al. Hydralazine-induced promoter demethylation enhances sarcoplasmic reticulum Ca2+ -ATPase and calcium homeostasis in cardiac myocytes. Lab Invest. 2011;91:12911297. doi:10.1038/labinvest.2011.92.

40. Bridgeman SC, Ellison GC, Melton PE, et al. Epigenetic effects of metformin: from molecular mechanisms to clinical implications. Diabetes Obes Metab. 2018;20(7):15531562. doi:10.1111/dom.13262.

41. Xiao H, Ma X, Feng W, et al. Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. Cardiovasc Res. 2010;87:504513. doi:10.1093/cvr/cvq066.

42. Zhao Q, Song W, Huang J, et al. Metformin decreased myocardial fibrosis and apoptosis in hyperhomocysteinemia -induced cardiac hypertrophy. Curr Res Transl Med. 2021;69:103270. doi:10.1016/j.retram.2020.103270.

43. Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system. Circ Res. 2017;120:229243. doi:10.1161/CIRCRESAHA.116.308537.

44. Sun F, Duan W, Zhang Y, et al. Simvastatin alleviates cardiac fibrosis induced by infarction via up-regulation of TGF- receptor III expression. Br J Pharmacol. 2015;172:37793792. doi:10.1111/bph.13166.

45. Gronda E, Jessup M, Iacoviello M, et al. Glucose metabolism in the kidney: neurohormonal activation and heart failure development. J Am Heart Assoc. 2020;9(23):e018889. doi:10.1161/JAHA.120.018889.

46. Lee HC, Shiou YL, Jhuo SJ, et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc Diabetol. 2019;18:45. doi:10.1186/s12933-019-0849-6.

47. Li C, Zhang J, Xue M, et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol. 2019;18:15. doi:10.1186/s12933-019-0816-2.

48. Arow M, Waldman M, Yadin D, et al. Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy. Cardiovasc Diabetol. 2020;19:7. doi:10.1186/s12933-019-0980-4.

49. Steven S, Oelze M, Hanf A, et al. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol. 2017;13:370385. doi:10.1016/j.redox.2017.06.009.

50. Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 Diabetes. N Engl J Med. 2016;374:1094. doi:10.1056/NEJMc1600827

51. Zamani P, Akers S, Soto-Calderon H, et al. Isosorbide Dinitrate, with or without hydralazine, does not reduce wave reflections, left ventricular hypertrophy, or myocardial fibrosis in patients with heart failure with preserved ejection fraction. J Am Heart Assoc. 2017;6:e004262. doi:10.1161/JAHA.116.004262.

52. Halabi A, Sen J, Huynh Q, et al. Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis. Cardiovasc Diabetol. 2020;19(1):124. doi:10.1186/s12933-020-01100-w.

53. Gu J, Yin ZF, Zhang JF, et al. Association between long-term prescription of metformin and the progression of heart failure with preserved ejection fraction in patients with type 2 diabetes mellitus and hypertension. Int J Cardiol. 2020;306:140145. doi:10.1016/j.ijcard.2019.11.087.

54. Marume K, Takashio S, Nagai T, et al. Effect of statins on mortality in heart failure with preserved ejection fraction without coronary artery disease. Report from the JASPER Study. Circ J. 2019;83:357367. doi:10.1253/circj.CJ-18-0639.

55. Lee MS, Duan L, Clare R, et al. Comparison of effects of statin use on mortality in patients with heart failure and preserved versus reduced left ventricular ejection fraction. Am J Cardiol. 2018;122:405412. doi:10.1016/j.amjcard.2018.04.027.

56. Lam CSP, Chandramouli C, Ahooja V, Verma S. SGLT-2 inhibitors in heart failure: current management, unmet needs, and therapeutic prospects. J Am Heart Assoc. 2019;8:e013389. doi:10.1161/JAHA.119.013389.

57. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819829. doi:10.1016/S0140-6736(20)31824-9.

58. Nishitani S, Fukuhara A, Shin J, et al. Metabolomic and microarray analyses of adipose tissue of dapagliflozin-treated mice, and effects of 3-hydroxybutyrate on induction of adiponectin in adipocytes. Sci Rep. 2018;8:8805. doi:10.1038/s41598-018-27181-y.

59. Wong AK, AlZadjali MA, Choy AM, et al. Insulin resistance: a potential new target for therapy in patients with heart failure. Cardiovasc Ther. 2008;26:203213. doi:10.1111/j.1755-5922.2008.00053.x.

60. Pantalone KM, Kattan MW, Yu C, et al. The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis. Acta Diabetol. 2009;46:145154. doi:10.1007/s00592-008-0090-3.

61. Papanas N, Maltezos E, Mikhailidis DP. Metformin and heart failure: never say never again. Expert Opin Pharmacother. 2012;13:18. doi:10.1517/14656566.2012.638283.

62. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:22482261. doi:10.1056/NEJMoa0706201.

63. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:12311239. doi:10.1016/S0140-6736(08)61240-4.

64. Alehagen U, Benson L, Edner M, et al. Association between use of statins and outcomes in heart failure with reduced ejection fraction: prospective propensity score matched cohort study of 21 864 patients in the Swedish Heart Failure Registry. Circ Heart Fail. 2015;8:252260. doi:10.1161/CIRCHEARTFAILURE.114.001730.

65. Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J Clin Pharmacol. 2013;75:645662. doi:10.1111/j.1365-2125.2012.04374.x.

66. Mohebi-Nejad A, Bikdeli B. Omega-3 supplements and cardiovascular diseases. Tanaffos. 2014;13:614.

67. Burdge GC, Lillycrop KA. Fatty acids and epigenetics. Curr Opin Clin Nutr Metab Care. 2014;17:156161. doi:10.1097/MCO.0000000000000023.

68. de la Rocha C, Prez-Mojica JE, Len SZ, et al. Associations between whole peripheral blood fatty acids and DNA methylation in humans. Sci Rep. 2016;6:25867. doi:10.1038/srep25867.

69. Heydari B, Abdullah S, Pottala JV, et al. Effect of omega-3 acid ethyl esters on left ventricular remodeling after acute myocardial infarction: the OMEGA-REMODEL randomized clinical trial. Circulation. 2016;134:378391. doi:10.1161/CIRCULATIONAHA.115.019949.

70. Block RC, Liu L, Herrington DM, et al. Predicting risk for incident heart failure with omega-3 fatty acids: from MESA. JACC Heart Fail. 2019;7:651661. doi:10.1016/j.jchf.2019.03.008.

71. Berezin A. Metabolic memory phenomenon in diabetes mellitus: achieving and perspectives. Diabetes Metab Syndr. 2016;10:S17683. doi:10.1016/j.dsx.2016.03.016.

72. Sommese L, Benincasa G, Lanza M, et al. Novel epigenetic-sensitive clinical challenges both in type 1 and type 2 diabetes. J Diabetes Complications. 2018;32:10761084. doi:10.1016/j.jdiacomp.2018.08.012.

73. Trum M, Wagner S, Maier LS, et al. CaMKII and GLUT1 in heart failure and the role of gliflozins. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165729. doi:10.1016/j.bbadis.2020.165729.

74. Nikolic M, Zivkovic V, Jovic JJ, et al. SGLT2 inhibitors: a focus on cardiac benefits and potential mechanisms. Heart Fail Rev. 2021. doi:10.1007/s10741-021-10079-9.

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76. Benincasa G, DeMeo DL, Glass K, Silverman EK, Napoli C. Epigenetics and pulmonary diseases in the horizon of precision medicine: a review. Eur Respir J. 2020 Nov 19:2003406. doi:10.1183/13993003.03406-2020.77.

77. Benincasa G, Marfella R, Della Mura N, et al. Strengths and opportunities of network medicine in cardiovascular diseases. Circ J. 2020 Jan 24;84(2):144152. doi:10.1253/circj.CJ-19-0879.

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Epigenetic therapies for heart failure | VHRM - Dove Medical Press

A passion for the natural world drives many of our adventures. And when were not actually outside, we love delving into the discoveries about the places where we live and travel. Here are some of the best natural history links weve found this week.

Elephants are dying in droves in Botswana: Between January and March 2021, 39 Africa elephants turned up dead in Botswana. All deaths occurred in the Moremi Game Reserve, the same region where 350 elephants died in mid-2020. Preliminary results indicate that cyanobacteria toxins are to blame. Water sources in the area are becoming warmer, creating an environment in which the toxic cyanobacteria thrive.

Scientists have grown a mini beating heart: Researchers in Vienna have grown tiny 3D heart-like organs in the lab. Made from human stem cells, the organoids, as theyre called, are the size of a sesame seed and beat the same way our hearts do. Unlike previous efforts that required artificial scaffolding, these cells organized themselves to grow a hollow chamber. Scientists hope that the mini-hearts will provide a better understanding of how the cardiac system responds to disease.

The largest iceberg in the world. Photo: ESA/Earth Observation

Worlds largest iceberg breaks away from Antarctic ice shelf: An iceberg bigger than Majorca has broken away from the Ronne Ice Shelf into the Weddell Sea. Unimaginatively named A-76, the iceberg is 4,320 square kilometres in area and is currently the largest iceberg in the world. Of course, it is bigger than Rhode Island, the standard comparison for such giant objects. The Antarctic region from which it comes is generally unaffected by climate change. [The break-off] is part of a natural cycle, says Alex Brisbourne, a glaciologist at the British Antarctic Survey.

Scientists dig deepest ocean hole in history: Researchers off the coast of Japan have drilled the deepest ocean hole in the history in the Pacific Ocean. The hole reaches nine kilometres below the surface of the ocean. It took just two hours and 40 minutes for the giant piston corer to reach the bottom of the Japan Trench. The team extracted a 37m-long sediment core from the bottom of the sea. The site is very close to the epicentre of the 2011 Tohoku-oki earthquake, the largest ever to strike Japan. Scientists hope that the sediments will help them understand the regions earthquake history.

Researcher want to find out if tardigrades could survive in space. Photo: Forbes.com

Tardigrades shot from gun to see if they can survive space travel: Tardigrades, also known as water bears and moss piglets, are microscopic invertebrates that are found almost everywhere water exists. If required (by drought, for example), they are able to drain their cells of liquid and enter suspended animation. In this state, they can survive everything from subzero temperatures to radiation. Researchers have put the Tardigrades into nylon bullets and fired them at sand targets in a vacuum chamber at speeds of up to 1,000 metres per second to see if they could withstand being shot onto other planets.

Death Valley is no longer the hottest place on Earth: Death Valley has held the record for the worlds hottest air temperature since 1913 when Furnace Creek reached 56.7C. Recently, two locations have surpassed Death Valley at its hottest. Satellite data reveal that the Lut Desert in Iran and the Sonoran Desert along the Mexican-U.S. border have reached a sizzling 80.8C.

Rebecca is a freelance writer and science teacher based in the UK.

She is a keen traveler and has been lucky enough to backpack her way around Africa, South America, and Asia. With a background in marine biology, she is interested in everything to do with the oceans and aims to dive and open-water swim in as many seas as possible.

Her areas of expertise include open water sports, marine wildlife and adventure travel.

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Science Links of the Week Explorersweb - ExplorersWeb

Exosome therapeutic marketis expected to gain market growth in the forecast period of 2019 to 2026. Data Bridge Market Research analyses that the market is growing with a CAGR of 21.9% in the forecast period of 2019 to 2026 and expected to reach USD 31,691.52 million by 2026 from USD 6,500.00 million in 2018. Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

International Exosome Therapeutic market report offers the best market and business solutions to pharmaceutical industry in this rapidly revolutionizing market place to thrive in the market. Market definition of the document gives the scope of particular product with respect to the driving factors and restraints in the market. Competitor strategies such as new product launches, expansions, agreements, joint ventures, partnerships, and acquisitions can be utilized well by the pharmaceutical industry to take better steps for selling goods and services. Exosome Therapeutic market analysis report is a careful investigation of current scenario of the market and future estimations which spans several market dynamics.

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The major players covered in the report are evox THERAPEUTICS, EXOCOBIO, Exopharm, AEGLE Therapeutics, United Therapeutics Corporation, Codiak BioSciences, Jazz Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH, ReNeuron Group plc, Capricor Therapeutics, Avalon Globocare Corp., CREATIVE MEDICAL TECHNOLOGY HOLDINGS INC., Stem Cells Group among other players domestic and global. Exosome therapeutic market share data is available for Global, North America, Europe, Asia-Pacific, and Latin America separately. DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

Key questions answered in Exosome Therapeutic Report:

Scope of the Exosome Therapeutic Market

The global exosome therapeutic market is segmented on the basis of countries into U.S., Mexico, Turkey, Hong Kong, Australia, South Korea, Argentina, Colombia, Peru, Chile, Ecuador, Venezuela, Panama, Dominican Republic, El Salvador, Paraguay, Costa Rica, Puerto Rico, Nicaragua and Uruguay.

All country based analysis of the exosome therapeutic market is further analyzed based on maximum granularity into further segmentation. On the basis of type, the market is segmented into natural exosomes and hybrid exosomes. Based on source, the market is segmented into dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, urine and others. On the basis of therapy, the market is segmented into immunotherapy, gene therapy and chemotherapy. On the basis of transporting capacity, the market is segmented into bio macromolecules and small molecules. On the basis of application, the market is segmented into oncology, neurology, metabolic disorders, cardiac disorders, blood disorders, inflammatory disorders, gynecology disorders, organ transplantation and others. On the basis of route of administration, the market is segmented into pa oral and parenteral. On the basis of end user, the market is segmented into hospitals, diagnostic centers and research & academic institutes and others.

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Exosome Therapeutic Market Drivers:

Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

Increased number of exosome therapeutics as compared to the past few years will accelerate the market growth. Companies are receiving funding for exosome therapeutic research and clinical trials. For instance, In September 2018, EXOCOBIO has raised USD 27 million in its series B funding. The company has raised USD 46 million as series a funding in April 2017. The series B funding will help the company to set up GMP-compliant exosome industrial facilities to enhance production of exosomes to commercialize in cosmetics and pharmaceutical industry.

Availability of various exosome isolation and purification techniques is further creates new opportunities for exosome therapeutics as they will help company in isolation and purification of exosomes from dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, and urine and from others sources. Such policies support exosome therapeutic market growth in the forecast period to 2019-2026.

Exosome Therapeutic Market Restraints:

Increasing demand for anti-aging therapies will also drive the market. Unmet medical needs such as very few therapeutic are approved by the regulatory authority for the treatment in comparison to the demand in global exosome therapeutics market will hamper the market growth market.

TOC of Exosome Therapeutic Market Report Contains:

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Customization Available:Global Exosome Therapeutic Market

Data Bridge Market Researchis a leader in advanced formative research. We take pride in servicing our existing and new customers with data and analysis that match and suits their goal. The report can be customised to include price trend analysis of target brands understanding the market for additional countries (ask for the list of countries), clinical trial results data, literature review, refurbished market and product base analysis. Market analysis of target competitors can be analysed from technology-based analysis to market portfolio strategies. We can add as many competitors that you require data about in the format and data style you are looking for. Our team of analysts can also provide you data in crude raw excel files pivot tables (Factbook) or can assist you in creating presentations from the data sets available in the report.

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Global Exosome Therapeutic Market Updates, Future Growth, Industry Analysis and Comprehensive Study on Key Players-ReNeuron Group plc, Capricor...

The Induced Pluripotent Stem Cells market is expected to grow at a CAGR of 8.77% and is poised to reach $XX Billion by 2027 as compared to $XX Billion in 2020. The factors leading to this extraordinary growth is attributed to various market dynamics discussed in the report. Our experts have examined the market from a 360 degree perspective thereby producing a report which is definitely going to impact your business decisions.In order to make a pre-order inquiry, kindly click on the link below:-https://decisivemarketsinsights.com/induced-pluripotent-stem-cells-market/93040505/pre-order-enquiry

Key Companies Operating in this Market

Thermo Fisher Scientific Inc., FUJIFILM Corporation, Horizon Discovery Ltd., Takara Bio Inc, Cell Applications, Inc., Lonza Group AG, Evotec A.G., ViaCyte, Inc., CELGENE CORPORATION, Fate Therapeutics, Astellas Pharma Inc.,

Market by Type(Hepatocytes, Fibroblasts, Keratinocytes, Amniotic Cells, Neuronal Cells, Cardiac Cells, Vascular Cells, Immune Cells, Renal Cells, Liver Cells, Others

Market by ApplicationAcademic Research, Drug Development & Discovery, Toxicity Screening, Regenerative Medicine

The report initiated at DECISIVE MARKETS INSIGHTS describes the various business activities of a particular company to give the readers an overall idea about the process which a company follows to create an advantage for itself from a competitive angle thus depicting a thorough overall idea about the Value Chain analysis. Several effective strategies are prevailing in the current global Induced Pluripotent Stem Cells Market that can be implemented for effective organizational growth over the forecasted period of 2020-2027. Some of the key investment areas are thoroughly elucidated in the report as well as an overall idea about conducting the process of modern Induced Pluripotent Stem Cells Market evaluation is well-included.

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A technique known as Real-estate crowd funding is becoming immensely popular in the modern market nowadays. It is the process of raising an adequate amount of money for investment in the real estate sector of businesses worldwide by reaching out to a handful of investor groups for assistance with a little amount of money. A lot of effective strategies are implemented for promoting the overall market like email marketing, product promotion, affiliate marketing, and various other social media platforms.

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Long term strategic planning is very much essential for balanced and effective market growth as well as elucidating the techniques to properly identify the brands on which a huge amount of investment can be made to gain a significant advantage over the other existing competitors in the modern market thus delineating an in-depth BCG analysis. The report elaborates on the various restraints, consequences, constraints, and various threats of the global competitive market. Some of the major external factors that are highly responsible for influencing the modern market growth are broadly elucidated in the report such as political, economic, social, and major technological factors thus laying out an elaborate and in-depth PESTEL analysis of the modern global market. A deep understanding of the feasibility of a business is mandatory for the global leaders of the market before making any major step towards further business growth. To get an overall idea about that, the most necessary thing is a proper estimation of the frailty and strengths of the key market products of the respective businesses thus depicting a thorough and well-formed SWOT analysis. There are numerous ways to keep going parallel with the rapid growth rate of the modern global market. Many essential modern marketing pointers are elaborately inculcated such as substitution threats, tremendous bargaining power of both the suppliers and the consumers, etc. henceforth explaining broadly the Porter Five Force Model. There are a lot of valid touch points that exist between the consumers and global businesses which are needed to be efficiently figured out to get a clear idea about the entire scenario of the relationship between the consumer and suppliers. The report delineates a variety of approaches that can be followed to enhance the strength of this relationship at present as well as in the future, thereby elucidating an in-depth point-by-point analysis.

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Induced Pluripotent Stem Cells Market 2021 | Industry Scenario and Key Vendors Thermo Fisher Scientific Inc., FUJIFILM Corporation, Horizon Discovery...

Chimeric antigen receptor (CAR) T cell therapy is a new type of cancer treatment. During this treatment, healthcare professionals reprogram the immune system to attack cancer cells.

Healthcare professionals currently use CAR T therapy to treat some blood cancers. However, scientists are investigating whether or not it could also work in other cancers.

This article will explain what CAR T cell therapy is and how it works. It will also look at some possible side effects and the recovery process.

T cells are part of the immune system. They are a type of white blood cell with proteins on the surface that act as receptors.

T cells move around the blood, checking for foreign substances, such as viruses or bacteria. These foreign substances also have proteins on their surfaces. Experts call these proteins antigens.

Immune cell receptors and antigens fit together like a lock and key. Each foreign substance and T cell has a differently shaped antigen or receptor. T cells bind to antigens that fit their receptor, destroying the foreign substance.

Cancerous cells also have antigens. However, T cells rarely have the right receptor to bind to them.

CAR T cell therapy is a way of training the immune system to recognize cancerous cells. It is a type of gene or cell therapy.

Scientists add CARs to a persons T cells. These new receptors help the T cells bind and destroy cancerous cells.

Different cancers have different antigens, and scientists must adapt the treatment accordingly.

Success rates vary depending on the type of cancer a healthcare professional is using CAR T cell therapy to treat.

One 2017 review suggests that up to 90% of people with a specific form of leukemia fully recovered following this form of treatment.

However, the treatment is still very new. The Food and Drug Administration (FDA) approved the first CAR T cell therapy in 2017. So, there is still much to learn about how well it works.

Healthcare professionals may use CAR T cell therapy if traditional cancer treatments, such as chemotherapy, are ineffective or if the cancer returns.

The FDA have approved four CAR T cell therapies in the United States. Healthcare professionals can only use them to treat specific blood cancers in certain groups of people, as follows:

However, the U.S. National Library of Medicine list over 600 ongoing CAR T cell therapy clinical trials. Scientists are currently investigating the use of CAR T cell therapy in many types of cancer, including:

According to the American Cancer Society, receiving CAR T cell therapy can take a few weeks.

The process has three steps:

Healthcare professionals will collect the T cells through an intravenous (IV) line. This can take 23 hours.

Blood will flow from the persons body into a machine that will remove the white blood cells. T cells are a type of white blood cell. The machine will then send the rest of the blood back through another IV line.

Healthcare professionals will separate the T cells from the rest of the white cells and send them to a laboratory. Scientists will then add CARs to the cells, creating CAR T cells.

The scientists will wait for the cells to multiply enough to fight cancerous cells before returning them. This part of the process can take a few weeks.

The next stage will be to insert the new CAR T cells into the persons bloodstream through another IV line.

Healthcare professionals may recommend chemotherapy first to prepare the immune system for the new CAR T cells.

CAR T cell therapy can cause some side effects. The most common side effect is cytokine release syndrome (CRS).

Cytokines are chemical messengers in the immune system that support the T cells. Cytokines multiply when the CAR T cells enter the body, and this can lead to an overproduction of cytokines.

CRS can cause mild symptoms, including:

It can also cause some severe symptoms, such as:

Severe CRS can also lead to neurological problems, including:

Serious CRS can be very dangerous. People with severe CRS will need immediate treatment in intensive care. Most of the symptoms are reversible, but CRS can sometimes be fatal.

People will usually have to stay in the hospital for observation after CAR T cell therapy. The observation period varies from hospital to hospital, but it is usually a few weeks.

Side effects can develop 121 days after treatment. People are also at higher risk of infection for 2830 days after the infusion.

CAR T cell therapy is a new cancer treatment that trains the immune system to fight cancer cells. Scientists genetically modify T cells so that they can detect and fight cancerous cells. The treatment tends to be effective, but it also carries a risk of serious side effects.

CAR T cell therapy is a very new treatment that is currently only available for some blood cancers. However, hundreds of studies are currently investigating its use in other cancer types.

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CAR T cell therapy explained: Cancer types, success rate, and more - Medical News Today

Under the terms of the agreement, the CEO of the Cambridge headquartered Axol Bioscience, Liam Taylor, and the Axol senior leadership team, will take over the management of the merged businesses, with the intent to migrate the brand to Axol Bioscience.

Censos interim CEO, Dr Tom Stratford, was also appointed non-executive director of the combined board.

The new entity, according to the parties, will become a leading provider of products and services in iPSC-based neuroscience, immune cell, and cardiac modeling for drug discovery and screening markets, providing customers validated ready-to-use cell lines and a suite of services with broader expertise, robust functional data, and customization capabilities.

They also promise shorter lead times for clients. On that, Liam Taylor, CEO Axol, told BioPharma-Reporter: Doubling the size of the scientific and technical project team and moving into two sites means bandwidth for larger production scale on the product side and ability to run simultaneous projects.

The transaction was also accompanied by a fundraising round in excess of 3.8m (US$5.3m) across shareholders. The funding was led by EIS fund manager, Calculus Capita, and Par Equity, a VC firm, based in Edinburgh. Also involved in the financing of the merged entity were Jonathan Milner, founder and former CEO of Abcam and chair of the Axol Bioscience board, Intuitive Investment group, Scottish Enterprise, and SyndicateRoom.

The investment will be used to enable growth of the business along with new hires to meet customer demand.

The growth plan, said Taylor, is to increase the manufacturing scale of flagship products while keeping a robust R&D pipeline moving to productize new cell lines as well as those owned by Censo.

At the same time, the merged entity will grow through our ability to run simultaneous service projects across a greater [number of] areas. There will be limited recruitment, merely to fill current gaps in field commercial, scientific technicians and quality, he added.

Dr Milner said merging these two players in the iPSC space, which have complementary expertise and offerings, is the most direct and low risk path to gaining a more competitive market position. He said the deal will move both organizations from thriving start-ups to a more polished commercial entity that is able to meet aggressive demand increases.

Originally posted here:
UK deal sees consolidation of two players in the iPSC space - BioPharma-Reporter.com

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Mercks anti-PD-1 therapy, for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation in combination with platinum- and fluoropyrimidine-based chemotherapy. The approval is based on results from the Phase 3 KEYNOTE-590 trial, which demonstrated significant improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) for KEYTRUDA plus fluorouracil (FU) and cisplatin versus FU and cisplatin alone, regardless of histology or PD-L1 expression status. For OS and PFS, KEYTRUDA plus FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p<0.0001) and reduced the risk of disease progression or death by 35% (HR=0.65 [95% CI, 0.55-0.76]; p<0.0001) versus FU and cisplatin alone. The ORR, an additional efficacy outcome measure, was 45% (95% CI, 40-50) for patients who received KEYTRUDA plus FU and cisplatin and 29% (95% CI, 25-34) for those who received FU and cisplatin alone (p<0.0001).

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see Selected Important Safety Information below.

Because esophageal cancer generally has poor survival rates, new first-line therapies are urgently needed for these patients, said Dr. Peter Enzinger, Director, Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Womens Cancer Center. Todays approval of this indication for KEYTRUDA introduces a new option, which has shown a superior survival benefit compared to FU and cisplatin alone, for newly diagnosed patients with locally advanced or metastatic esophageal or GEJ carcinoma that is not amenable to surgical resection or definitive chemoradiation, regardless of PD-L1 expression status and tumor histology.

There have been few advances in improving survival outcomes in the first-line treatment setting for esophageal cancer over the last three decades, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. We are committed to putting patients first and continuing our research to help advance new approaches to potentially extend the lives of people with cancer. We thank all of the patients, their caregivers and healthcare professionals who participated in the study.

This approval was reviewed under the FDAs Real-Time Oncology Review (RTOR) pilot program and the FDAs Project Orbis, an initiative of the Oncology Center of Excellence that provides a framework for concurrent review of oncology drugs among its international partners. Under this project, the FDA, Australian Therapeutic Goods Administration, Health Canada and Swissmedic collaboratively reviewed the KEYNOTE-590 application. The application is still under review in Australia, Canada and Switzerland.

Data Supporting the Approval

The approval was based on data from KEYNOTE-590 (ClinicalTrials.gov, NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation. Patients were randomized (1:1) to receive either KEYTRUDA (200 mg on Day 1 every three weeks) or placebo (on Day 1 every three weeks) in combination with cisplatin (80 mg/m2 on Day 1 every three weeks for up to six cycles) plus FU (800 mg/m2 per day on Days 1 to 5 every three weeks, or per local standard for FU administration, for up to 24 months); all study medications were administered via intravenous infusion.

Randomization was stratified by tumor histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 vs. 1).

Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression. Patients could be treated with KEYTRUDA for up to 24 months in the absence of disease progression. The major efficacy outcome measures were OS and PFS, as assessed by the investigator according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ). The study pre-specified analyses of OS and PFS based on squamous cell histology, Combined Positive Score (CPS) 10, and in all patients. Additional efficacy outcome measures were ORR and duration of response (DOR), according to modified RECIST v1.1, as assessed by the investigator.

The study population characteristics were median age of 63 years (range: 27 to 94), 43% age 65 or older; 83% male; 37% white, 53% Asian and 1% Black; 40% had an ECOG PS of 0, and 60% had an ECOG PS of 1. Ninety-one percent had M1 disease, and 9% had M0 disease. Seventy-three percent had a tumor histology of squamous cell carcinoma, and 27% had adenocarcinoma.

The trial demonstrated statistically significant improvements in OS and PFS for patients randomized to KEYTRUDA in combination with chemotherapy compared to chemotherapy alone. Efficacy results showed:

Endpoint

KEYTRUDA + Cisplatin + FU(n=373)

Placebo + Cisplatin + FU(n=376)

OS

Number of events (%)

262 (70)

309 (82)

Median in months (95% CI)

12.4 (10.5, 14.0)

9.8 (8.8, 10.8)

Hazard ratio* (95% CI)

0.73 (0.62, 0.86)

p-value

<0.0001

PFS

Number of events (%)

297 (80)

333 (89)

Median in months (95% CI)

6.3 (6.2, 6.9)

5.8 (5.0, 6.0)

Hazard ratio* (95% CI)

0.65 (0.55, 0.76)

p-value

<0.0001

ORR

ORR, % (95% CI)

45 (40, 50)

29 (25, 34)

Number of complete responses (%)

24 (6)

9 (2.4)

Number of partial responses (%)

144 (39)

101 (27)

p-value

<0.0001

DOR

Median in months (range)

8.3 (1.2+, 31.0+)

6.0 (1.5+, 25.0+)

* Based on the stratified Cox proportional hazard model

Based on a stratified log-rank test

Confirmed complete response or partial response

Based on the stratified Miettinen and Nurminen method

In a pre-specified formal test of OS in patients with PD-L1 (CPS 10) (n=383), the median was 13.5 months (95% CI, 11.1-15.6) for the KEYTRUDA arm and 9.4 months (95% CI, 8.0-10.7) for the placebo arm, with a HR of 0.62 (95% CI, 0.49-0.78; p<0.0001). In an exploratory analysis, in patients with PD-L1 (CPS <10) (n=347), the median OS was 10.5 months (95% CI, 9.7-13.5) for the KEYTRUDA arm and 10.6 months (95% CI, 8.8-12.0) for the placebo arm, with a HR of 0.86 (95% CI, 0.68-1.10).

In the study, the median duration of exposure was 5.7 months (range: 1 day to 26 months) in the KEYTRUDA combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm. KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (1%) were pneumonitis (1.6%), acute kidney injury (1.1%) and pneumonia (1.1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 67% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (2%) were neutropenia (19%), fatigue/asthenia (8%), decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%) and nausea (2.2%). The most common adverse reactions (all grades 20%) for KEYTRUDA plus chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%) and weight loss (24%).

About Esophageal Cancer

Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. In the U.S., about 67% of newly diagnosed esophageal cancer cases were adenocarcinoma, and 33% were squamous cell carcinoma. It is estimated there will be approximately 19,260 new cases of esophageal cancer diagnosed and about 15,530 deaths resulting from the disease in the U.S. in 2021.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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FDA Approves Merck's KEYTRUDA (pembrolizumab) Plus Platinum- and Fluoropyrimidine-Based Chemotherapy for Treatment of Certain Patients With Locally...

Stem Cell Therapy Market: Snapshot

Of late, there has been an increasing awareness regarding the therapeutic potential of stem cells for management of diseases which is boosting the growth of the stem cell therapy market. The development of advanced genome based cell analysis techniques, identification of new stem cell lines, increasing investments in research and development as well as infrastructure development for the processing and banking of stem cell are encouraging the growth of the global stem cell therapy market.

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One of the key factors boosting the growth of this market is the limitations of traditional organ transplantation such as the risk of infection, rejection, and immunosuppression risk. Another drawback of conventional organ transplantation is that doctors have to depend on organ donors completely. All these issues can be eliminated, by the application of stem cell therapy. Another factor which is helping the growth in this market is the growing pipeline and development of drugs for emerging applications. Increased research studies aiming to widen the scope of stem cell will also fuel the growth of the market. Scientists are constantly engaged in trying to find out novel methods for creating human stem cells in response to the growing demand for stem cell production to be used for disease management.

It is estimated that the dermatology application will contribute significantly the growth of the global stem cell therapy market. This is because stem cell therapy can help decrease the after effects of general treatments for burns such as infections, scars, and adhesion. The increasing number of patients suffering from diabetes and growing cases of trauma surgery will fuel the adoption of stem cell therapy in the dermatology segment.

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

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Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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Stem Cell Therapy Market Evaluation of Industry Trends, Growth Drivers and Forecast To 2025 NeighborWebSJ - NeighborWebSJ

INTRODUCTION

Myocardial infarction (MI) remains one of the leading causes of death worldwide. The inflammatory response caused by MI sets the stage for fibrous tissue and often progresses to chronic heart failure (1), resulting in a more than 50% 5-year mortality after MI (2). An immunomodulation strategy, which prevents an excessive inflammatory response, can be beneficial to reduce scar tissue formation. Immunomodulation alone can likely prevent ongoing damage but fails to restore the compromised heart function. Promoting angiogenesis in the infarct area has the potential to reperfuse and salvage the surviving ischemic myocardium (3). Therefore, we hypothesize that long-term improvements in heart function after MI can be achieved by the combination of resolving inflammation and promoting angiogenesis in the infarct area.

Various therapeutics, such as cell transplant, exosomes, and nucleic acids, have been explored to treat MI and restore cardiac function, with varying degrees of success. Cell transplantation could enhance the functions of the infarcted heart (4), but only cardiomyocytes derived from pluripotent stem cells have been shown to engraft and generate functional myocardium (5). Limitations in cell sources, potential immune responses, and rigorous regulations hinder the clinical translation of cell-based therapies. Several studies have shown that cell-derived exosomes may be effective in treating cardiovascular diseases (6). However, there are obvious variations in exosomes resulting from multiple factors such as cell phenotype, preparation procedure, and exosome storage conditions (7). MicroRNAs (miRNA) are appealing genetic tools to stimulate cardiac performance, as they could regulate the levels of multiple genes simultaneously. Recently, it has been suggested that the cardiovascular system is regulated via a miRNA network (8). High-throughput screening work revealed that miRNAs, particularly microRNA-21-5p (miR-21-5p), are highly expressed in endothelial cells and stimulate angiogenesis by targeting antiangiogenic genes (9). miRNAs have a unique capacity to simultaneously promote the secretion of multiple endogenous molecules that might enhance vessel regeneration in the ischemic tissue. Negatively charged miRNAs typically cannot cross the cell membrane without a transfection agent. In addition, miRNAs are relatively unstable and can be degraded rapidly in vivo (10). Thus, vectors that protect and deliver miRNAs into cells are crucial to improve the efficacy of miRNA therapy.

Mesoporous silica nanoparticles (MSNs) have been developed as a promising vector for miRNA delivery because of their many excellent properties, such as good biocompatibility and high transfection efficiency. Moreover, studies have shown that inflammation can be modulated by phagocytosis of micro/nanomaterials, such as liposomes (11), polymer particles (12, 13), and inorganic particles (14). Macrophages play a central role in regulating infarct-induced inflammation because they adopt proinflammatory (M1) phenotypes. In this study, we found that MSNs showed great potential in inhibiting M1 polarization following inflammation both in vitro and in vivo (see details in Results). Therefore, we engineered an MSN/miR-21-5p complex by combining MSN, a potential anti-inflammatory nanomaterial, and miR-21-5p, a proangiogenic therapeutic.

RNA interference (RNAi) is a promising therapeutic approach for various diseases (15). An important aspect in RNAi delivery system design is to ensure precise spatiotemporal release (1621). Uncontrolled delivery of miRNA in the heart could result in sudden arrhythmia, as reported by Gabisonia et al. (22). In addition, studies have also identified that a big challenge for RNAi-based therapeutics is to achieve highly localized RNAi delivery (16, 18, 19, 23). Drug release from conventional hydrogels (24, 25) is controlled by passive diffusion and often results in off-target effects (26). In contrast, MSN/miR-21-5p complexes were conjugated within an injectable hydrogel matrix via pH-responsive bonds to form Gel@MSN/miR-21-5p, which accurately released MSN/miR-21-5p complexes only in the acidic infarct area.

Here, we designed an injectable hydrogel loaded with MSN/miR-21-5p complexes (Gel@MSN/miR-21-5p) to deliver miR-21-5p in a two-stage mechanism: The first stage comprises pH-triggered on-demand delivery of MSN/miR-21-5p complexes from the hydrogel matrix in acidic infarct areas, and the second stage involves intracellular delivery of miR-21-5p from MSN/miR-21-5p complexes. This drug delivery system is designed to harness the synergy of inflammation suppression and angiogenesis enhancement in treating MI, the efficacy of which was evaluated in a clinically relevant MI swine model.

Amino (-NH2) and trimethylamine [-N(CH3)3, TMA] functionalized MSNs (MSN-NH2-TMA) were first synthesized (fig. S1A), which had positive charges for miRNA loading (fig. S1B). The miRNA-loading capacity of the MSN-NH2-TMA complex was quantitatively evaluated by a gel retardation assay and potential measurements (fig. S1C), which showed complete encapsulation of miRNA when the mass ratio between the MSN-NH2-TMA complex and miRNA increased to 10:1. Subsequent studies were all using MSN/miRNA complexes with this ratio. Direct evidence of miRNAs loading in MSNs was also provided by transmission electron microscopy (fig. S1D) and energy-dispersive x-ray spectroscopy (EDS) analysis (fig. S1E), which revealed obvious miRNAs residing in MSN pores and signals corresponding to the element P from loaded miRNAs.

Gel@MSN/miR-21-5p was fabricated by mixing the MSN/miR-21-5p complex aqueous solution (30 wt%) with an aqueous solution of -CD (66.7 mg/ml) and aldehyde-capped polyethylene glycol (PEGCHO; 66.7 mg/ml). The hydrogel matrix had a porous structure with pore sizes of around 10 m in diameter and MSN/miR-21-5p complexes covering the wall surface (fig. S1F). Scanning electron microscope image of the injectable colloidal hydrogel (Gel@MSN) showed plenty of MSNs conjugated in the hydrogel (red arrows). The presence of MSNs was also confirmed by EDS, which showed an obvious elemental signal of Si (fig. S1G). Hydrogel formation resulted from two interactions (fig. S2): (i) hydrophobic interaction between cyclodextrins (CDs) along the PEGCHO chains (27) and (ii) Schiff base between the NH2 group from MSNs and the aldehyde (CHO) group from PEGCHO/CD complexes. The stepwise gelation was confirmed by comparing different gelation processes between the MSN/PEGCHO/CD (group with both Schiff base and hydrophobic interaction) and control groups (PEG/MSN, group without hydrophobic interactions and Schiff bases; PEG/MSN/CD, group only with hydrophobic interactions) (fig. S3A) as well as the different rheological characterization of the resulting hydrogels (fig. S3, B and C). The cross-linking relies on hydrophobic and Schiff interactions, which are relatively weaker than conventional covalent bonds. The liquid-gel transition takes approximately 5 min, after which point the hydrogel is injected into the infarct area. The weak interaction allows the hydrogel to exhibit a shear-thinning property, which permitted it to switch from hydrogel to fluid during injection and subsequently formed a firm hydrogel at the MI area along with the further cross-linking process (fig. S3D). The retention property of the hydrogel in the beating heart was also evaluated. During bench testing, hydrogel (labeled with blue dye) was injected into myocardium tissue, and no detachment or cracks were observed between the hydrogel and tissue after bending, distorting, long-time immersing underwater, or stretching (fig. S3E).

The MSN/miRNA complexes were conjugated onto an injectable hydrogel by Schiff bonds. The Schiff base bond is stable at pH 7.4 but is disrupted in an acidic environment (pH 6.8) (fig. S3, F to H), enabling an on-demand release of MSN/miRNA (step 3 in fig. S2B) (28, 29). The 1H NMR (nuclear magnetic resonance) of 1,6-diaminohexane (HDA) functionalized PEG with Schiff base in between (HDA-PEG-HDA) after incubation in phosphate-buffered saline (PBS) buffer with pH 7.4 (red line) and pH 6.8 (black line) for 24 hours, which presented a clear proton peak of aldehyde only in the pH 6.8 treated group, demonstrating the high stability of Schiff base bonds at pH 7.4 and its gradual cleavage to form an aldehyde group at an acidic environment (fig. S3F). The gel permeation chromatography results of HDA functionalized PEG with Schiff base in between (HDA-PEG-HDA) after incubation in PBS buffer with pH 7.4 (i) and pH 6.8 (ii) for 24 hours, which presented an obvious drop of molecule weight only in the pH 6.8 treated group. Moreover, the molecule weight loss is close to twice the molecule weight of HDA, indicating the separation of HDA with PEG, due to the break of Schiff base (fig. S3H). These data comprehensively demonstrated the high stability of Schiff base bonds at pH 7.4 and its gradual cleavage at the slightly acidic environment.

The on-demand release profile was characterized in PBS buffer with pH 7.4 and pH 6.8 [which respectively simulated the microenvironment of healthy tissue (pH 7.4) and infarcted myocardium (pH 6.8)] (30, 31). There was a sustained release of MSN/miRNA complexes from the hydrogel matrix with ~75% release after 7 days at pH 6.8 (fig. S3I). In contrast, only ~6% MSN/miRNA was released from the hydrogel after 7 days at pH 7.4, which could be attributed to the diffusion of MSN/miR-21-5p at the different hydrogel degradation rates under different pH conditions (fig. S3I). The miRNA release from the MSN/miRNA complexes is presented in fig. S3J, which shows that a further decrease in the pH value to 5 (simulated intracellular endosomes and lysosomes environment) (32) could trigger miRNA release from MSN/miRNA complexes, leading to a cumulative release of miRNA of up to 60% over 48 hours.

Hydrogel degradation in vitro was monitored by measuring dry weight loss as a function of time following incubation in PBS (pH 6.8) at 37C (fig. S3K). As shown in fig. S3K, Gel@MSN/miRNA lost approximately 93% of the initial gel mass within 20 days. For in vivo measurements, the PEG frame of the hydrogel was labeled by fluorescent dye. Following injection, the fluorescence signal in the injected area was detected at the indicated time points. Figure S4 shows that the fluorescence signal decay is down to 67% at day 3 and 16% at day 14. At day 28, we could not detect any fluorescence signal, indicating that the hydrogel was completely degraded.

The retention of MSNs in vivo was monitored by fluorescence in vivo imaging system (IVIS) imaging at the indicated time points. Figure S5 shows that the fluorescence signal decay is down to 54% at day 3, 18% at day 14, and 2% at day 28, indicating that accumulation of MSNs was gradually decreased at tissue. At day 36, no positive signal was observed, indicating that almost no residual MSNs could be detectable at tissue.

To assess the in vitro uptake of the MSN/miR-21-5p complex by endothelial cells, the miR-21-5p was labeled with Cy3 (orange-red), the MSNs were labeled with fluorescein isothiocyanate (FITC) (green), and the cell nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI) (blue). For in vitro uptake analysis, endothelial cells were cocultured with MSN/miR-NC complexes or MSN/miR-21-5p complexes. The confocal images and quantification analysis showed that MSN/miR-21-5p complexes showed high transfection efficiency of miR-21-5p and resulted in an approximately 37-fold enhanced miR-21-5p levels in endothelial cells compared to that of control cells (Fig. 1, A and B). Representative profiles from the flow cytometry analysis revealed that the CD31 expression level was 96.5% in endothelial cells (Fig. 1C). Flow cytometry analysis indicated that more than 70% of endothelial cells internalized the MSN/miR-21-5p complexes (identified by the CD31+Cy3+) (Fig. 1D). The cytokine levels were determined by Western blot and real-time quantitative polymerase chain reaction (PCR) assay. Figure 1E shows that compared to the endothelial cell group and the MSN/miR-NCtreated group, MSN/miR-21-5p significantly promoted the expression of proangiogenic cytokines (VEGFA and PDGF-BB) from endothelial cells. MSN/miR-21-5ptreated endothelial cells also had increased capillary tube network formation (as measured by branch points and total tube length via tube formation assay) (as shown in Fig. 1G). We then simulated serum-free and hypoxic infarct-like conditions in vitro to assess the protective effect of MSN/miR-21-5p on the hypoxia/ischemia-induced cardiomyocyte apoptosis (Fig. 1H). The cardiomyocytes were exposed to a combination of ischemic/hypoxic conditions for 24 hours. Endothelial cells were pretreated with MSN/miR-21-5p or MSN/miR-NC and then cocultured with cardiomyocytes subjected to hypoxia/ischemia. Notably, at 24 hours of coculture, we found that coculture with MSN/miR-21-5ptreated endothelial cells reduced the apoptosis of hypoxia/ischemia-induced cardiomyocytes. This correlated with increased secretion of proangiogenic cytokines (VEGFA and PDGF-BB) from endothelial cells treated with MSN/miR-21-5p (Fig. 1, I and J). Previous studies demonstrated that VEGFA or PDGF-BB inhibits apoptosis (33, 34). These data may suggest that miR-21-5pinduced expression of proangiogenic factors in endothelial cells could prevent cardiomyocytes from undergoing apoptosis under ischemic and hypoxic conditions.

(A) In vitro uptake of the MSN/miR-21-5p complex by adherent endothelial cells (ECs) and macrophages (MCs). (B) In vitro transfection efficiency of miR-21-5p was determined by quantifying the miRNA level using real-time quantitative PCR. (C) Representative flow cytometry analysis of CD31 levels in ECs and F4/80 levels in MCs. (D) In vitro uptake of the MSN/miR-21-5p complex by ECs and MCs was determined by quantifying the double-positive cells (CD31 or F4/80 and Cy3) using flow cytometric analysis. The protein expression levels of VEGFA and PDGF-BB in endothelial cells (E) and tumor necrosis factor- (TNF-), interleukin-1 (IL-1), and IL-6 in macrophages (F) were determined by the real-time quantitative PCR and Western blot analysis. (G) The endothelial cells that formed three-dimensional (3D) capillary-like tubular structures were evaluated at indicated times (8 and 16 hours). (H) Schematic diagram of the experimental setup. TUNEL, terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick end labeling. (I) Apoptosis-positive cardiomyocytes from these treatment groups were further quantified. (J) Protein levels of secreted proangiogenic factors were determined by enzyme-linked immunosorbent assay (ELISA) analysis of cell supernatants from the MSN/miRNA-treated ECs (scale bars, 50 m). *P < 0.05 and ***P < 0.01. All experiments were carried out in triplicate. n = 5 per group. The data are shown as means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

To understand the in vitro immunomodulatory effect of MSN/miR-21-5p complexes, MSN/miR-NC complexes or MSN/miR-21-5p complexes were cocultured with isolated macrophages. MSNs were labeled with FITC (green), and miR-21-5p was labeled with Cy3 (red). Representative profiles from the flow cytometry analysis revealed that the F4/80 expression level was 98.2% in isolated macrophages (Fig. 1C). The confocal images and quantification analyses showed that MSN/miR-21-5p complexes had high uptake efficiency in macrophages. Flow cytometry analysis indicated that more than 80% of macrophages took up the MSN/miR-21-5p complexes (identified by the F4/80+Cy3 + staining pattern) (Fig. 1D). We then examined whether the uptake of the MSN/miR-21-5p complexes by macrophages could reduce the inflammatory response. For this purpose, a proinflammatory response was induced by injection of lipopolysaccharide (LPS), a potent inducer of inflammatory response (35), into the peritoneum of mice, and macrophages from the treated mice were collected. Figure 1F shows that the inflammation of the LPS-treated macrophages (LPS-macrophages) was markedly suppressed following uptake of the MSN/miR-21-5p complexes, as indicated by the notable decrease in the expression of tumor necrosis factor- (TNF-), interleukin-1 (IL-1), and IL-6, which are typical cytokines involved in the inflammatory response. These data suggest that the MSN/miR-21-5p complexes released from Gel@MSN/miR-21-5p simultaneously reduced proinflammatory cytokines and increased proangiogenic factors in vitro. The enhanced proangiogenic factors from endothelial cells could effectively prevent cardiomyocytes from apoptosis under ischemic and hypoxic conditions.

To obtain insight into the mechanism by which the MSN/miR-21-5p complex acts on macrophages to modulate the immune response, we performed a proteome analysis of protein alterations in macrophages. We collected three replicates of LPS-induced macrophages (inflammatory stage macrophages) treated with MSN/miR-NC, MSN/miR-21-5p, or pure MSNs. Untreated LPS-macrophages were used as a negative control. We used a label-free quantitative proteomic approach. Hierarchical clustering analysis of the data revealed that the protein expression patterns of the three treatment groups (MSN/miR-NC, MSN/miR-21-5p, or pure MSNs) were obviously different from that of LPS-macrophages without treatment, while the protein expression patterns of the three groups were similar (Fig. 2A). This consistently indicated that the function of immunomodulation originates from the MSNs themselves.

(A) A heatmap of selected proteins representing major altered signaling pathways in three datasets of macrophages treated with MSNs, MSN/miR-NC, or MSN/miR-21-5p complexes. Macrophages with no treatment were used as a negative control. The color bar indicates normalized z score intensity-based absolute quantification. (B) KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis of both up- and down-regulated pathways in macrophages after MSN treatment. The most significant pathways in the phosphoproteome are plotted on the x axis as the log10 of the P value, compared with the proteome. (C) KEGG pathway map of Toll-like signaling pathway. Proteins shown with red backgrounds are down-regulated in macrophages after MSN complex treatments when compared with macrophages with no treatment, as determined by pathway analysis. (D) Real-time quantitative PCR and Western blot analysis of TLR1, TLR2, TLR3, TLR8, P-NFB, TNF-, IL-1, and IL-6 protein content alteration in macrophages after treatment with MSNs, MSN/miR-NC, or MSN/miR-21-5p complexes. (E) Real-time quantitative PCR and Western blot analysis of P-NFB, TNF-, IL-1, and IL-6 protein content alteration in MSN/miR-21-5p complextreated macrophages that overexpress TLR2 with the TLR2 overexpression vector. ***P < 0.01. n = 3 per group. The data are shown as means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Current reports showed that the reduced inflammatory response elicited by MSN resulted from the reduction of transcription factor nuclear B (NFB), caspase-3, and IL-12 (36). The NFB signaling plays a major role in innate immunity and inflammatory responses. It was shown that the NFB signaling pathway plays important roles in MSN-regulated inflammation (37), but the exact mechanism leading to this effect was still obscure.

The present study used the GSEA (gene set enrichment analysis) method to examine the distribution of the functionally related KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway gene sets within the ranked gene list. GSEA showed that there were groups of genes negatively correlated with the immune response after MSN treatments. The majority of genes that were differentially expressed in macrophages after MSN treatments were enriched in several pathways, such as neutrophil degranulation, Toll-like receptor (TLR) signaling pathway, and MyD88 deficiency (Fig. 2B). TLR activation and MyD88 (a downstream adapter of TLR pathways) play important roles in the NFB signaling pathway (37), stimulation of which may lead to activation of NFB signaling and eventually lead to proinflammatory responses and progression to fibrous tissues (38, 39).

We found that abundance of proteins (TLR1, TLR2, TLR4, TLR3, TLR7, TLR8, TLR9, CD14, RAC1, and TAB1) involved in TLR signaling was down-regulated in macrophages after MSN treatments, indicating that TLR signal transduction pathway activity decreased in response to MSN treatment (Fig. 2C). The most significantly down-regulated genes are TLR1, TLR2, TLR3, and TLR8, which had more than threefold change.

To gain further insight into the mechanism by which MSNs modulated the immune response through the TLR signaling pathway, we examined protein alterations of TLR1, TLR2, TLR3, and TLR8 within macrophages after MSN treatment (Fig. 2D). We found that the mRNA and protein expressions of TLR1, TLR2, TLR3, and TLR8 cytokines were substantially lower in all MSN-treated groups. Meanwhile, NFB signaling pathway and downstream proinflammatory cytokines (TNF-, IL-1, and IL-6) were inhibited, which is consistent with previous findings that TLRs act as primary sensors that elicit innate immune responses and activate NFB signaling (Fig. 2D). Among the known TLRs, TLR2 has been characterized extensively as an inducer of proinflammatory cytokines. To determine whether MSNs modulated the immune response by down-regulating TLR2, we first treated macrophages with MSNs and then transfected MSN-treated macrophages with a TLR2 overexpression plasmid vector or empty vectors. We found that the NFB signaling pathway was up-regulated in macrophages transfected with the TLR2 overexpression vector compared to the empty vector control group. Consistently, the amounts of TNF-, IL-1, and IL-6 protein in macrophages were increased by transfection with the TLR2 overexpression vector (Fig. 2E). These comprehensive data suggest that MSNs modulated immune response through down-regulating TLR2, which inhibited the activation of NFB signaling and subsequently decreased the release of proinflammatory cytokines (TNF-, IL-1, and IL-6) (fig. S6).

To obtain insight into the mechanism underlying miR-21-5penhanced angiogenesis, we performed a proteogenomic analysis of protein alterations in endothelial cells after miR-21-5p treatment. We collected three replicates of endothelial cells after treatment with MSN/miR-NC or MSN/miR-21-5p. We applied a label-free quantitative proteomic approach. Hierarchical clustering analysis of the data revealed that the genes could be assigned into two groups based on their protein expression patterns, and the assigned groups matched with the groups by treatment (Fig. 3A). GSEA revealed that there were groups of genes positively correlated with angiogenesis after MSN/miR-21-5p treatment. KEGG analysis suggested that the MSN/miR-21-5p treatment groups were positively associated with key angiogenic signaling pathways (Fig. 3B). Compared to MSN/miR-NCtreated endothelial cells, MSN/miR-21-5ptreated endothelial cells had a larger number of proteins enriched in pathways such as vascular endothelial growth factor (VEGF) signaling pathway and platelet-derived growth factor (PDGF) signaling pathway (Fig. 3B). VEGF is the major mediator in endothelial cells and is considered to be a crucial signal transducer in angiogenesis. The binding of VEGF to the VEGF receptor leads to a cascade of signaling pathways, including ERK-MAPK (extracellular signalregulated kinase/mitogen-activated protein kinase) signaling, which particularly plays a central role in angiogenesis. Therefore, we focused on ERK-MAPK signaling in MSN/miR-21-5ptreated endothelial cells and found that the levels of phospho-Erk1/2, phospho-FAK, phospho-P38, phospho-AKT, VEGFA, and PDGF-BB were up-regulated in the MSN/miR-21-5p treatment group compared to the MSN/miR-NC group, indicating that miR-21-5p could enhance VEGFA expression and subsequently lead to ERK-MAPK signaling activation (Fig. 3C).

(A) A heatmap of selected proteins representing strongly altered signaling pathways in three datasets of endothelial cells treated with MSN/miR-NC or MSN/miR-21-5p complexes. (B) KEGG pathway analysis of both up- and down-regulated pathways in endothelial cells after MSN/miR-21-5p complex treatment. (C) Western blot analysis of changes in SPRY1, P-ERK1/2, P-FAK, P-p38, P-AKT, VEGFA, and PDGF-BB protein content alteration in endothelial cells after treatment with the MSN/miR-21-5p complex. (D) The effect of MSN/miR-21-5p or MSN/miR-NC on SPRY1 mRNA levels (left) and SPRY1 protein levels (right) in endothelial cells. (E) Schematic diagram illustrating the design of luciferase reporters with the WT SPRY1 3 untranslated region (WT 3UTR) or the site-directed mutant SPRY1 3UTR (3UTR-Mut). (F) The effect of MSN/miR-21-5p on luciferase activity in endothelial cells transfected with either the WT SPRY1 3UTR reporter (left) or the mutant SPRY1 3UTR reporter (right). (G) Western blot analysis of P-ERK1/2, P-FAK, P-p38, P-AKT, VEGFA, and PDGF-BB protein level alteration in MSN/miR-21-5p complextreated endothelial cells after overexpressing SPRY1 with the SPRY1 overexpression vector. *P < 0.05 and ***P < 0.01. n = 3 per group. The data are shown as means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

To gain further insight into the mechanism by which miR-21-5p promotes angiogenesis, we used a miRNA database to predict the potential target genes of miR-21-5p and found that SPRY1 has a miR-21-5p binding site in its 3 untranslated region (UTR). The amount of SPRY1 protein in endothelial cells was down-regulated by MSN/miR-21-5p treatment but not by MSN/miR-NC treatment, whereas we found no difference in SPRY1 mRNA levels between the two groups (Fig. 3D). To determine whether miR-21-5p functionally targets SPRY1 to promote angiogenesis, we overexpressed SPRY1 in endothelial cells. We found that phospho-Erk1/2, phospho-FAK, phospho-P38, phospho-AKT, VEGFA, and PDGF-BB levels were down-regulated in MSN/miR-21-5ptreated endothelial cells transfected with SPRY1 overexpression plasmid vector, compared to cells transfected with the empty vector (Fig. 3E). To test whether miR-21-5p directly targets SPRY1, we constructed luciferase reporters that had either the wild-type (WT) SPRY1 3UTR or an SPRY1 3UTR containing mutations at the miR-21-5p binding site (Fig. 3F). First, we found that MSN/miR-21-5p, but not MSN/miR-NC, substantially inhibited the luciferase reporter activity of the WT SPRY1 3UTR. Second, the luciferase reporter activity of the SPRY1mRNA with the mutated 3UTR was not suppressed by MSN/miR-21-5p (Fig. 3G). These comprehensive data suggest that delivery of miR-21-5p using MSN/miR-21-5p complexes promotes angiogenesis by targeting SPRY1 and subsequently activating the VEGF-induced ERK-MAPK signaling pathway (fig. S6). Detailed predicted miR-21-5p targets by Venn diagram analysis were revealed in fig. S7.

The in vivo efficacy of Gel@MSN/miR-21-5p was evaluated in an induced MI swine model. Coronary arteries were identified and ligated to induce a uniform and consistent MI, and the morphology and pumping effectiveness of the heart were evaluated ~45 min after the MI induction. The MI animals were then randomly divided into four groups receiving saline (negative control), agomiR-21-5p (a commercially available agent used to up-regulate endogenous miR-21-5p level), Gel@MSN/miR-NC, and Gel@MSN/miR-21-5p injection. Sham-operated animals served as a positive control. Morphological and functional assessments were performed using the modified Simpson method, which can accurately calculate left ventricular ejection fraction (LV EF) to detect any early echocardiographic changes. Changes in the morphology and pumping effectiveness of the heart were assessed through measurements of LV end diastolic volume (LVEDV), LV end systolic volume (LVESV), EF, and LV end diastolic dimension (LVEDd). Representative echocardiography images of short-axis views for each treatment group at baseline (before MI) and 45 min, 14 days, and 28 days after MI are shown in Fig. 4A. MI caused a substantial reduction in LV function 45 min after induction, as indicated by an absolute 20% decline in the EF. The morphological and functional parameters were slightly improved in the agomiR-21-5p and Gel@MSN/miR-NC groups compared with the saline negative control group at 14 and 28 days after MI, indicating that either miR-21-5p or MSNs alone could improve the morphology and pumping effectiveness of the heart but only to a limited degree (~an absolute 4 to 5% increase in EF values at 28 days, as compared to the saline group). More substantial improvement was achieved in the Gel@MSN/miR-21-5p group, with an approximately absolute 10% increase in the LV EF values at 28 days after MI. Time course echocardiography assessment over the 28-day study period is shown in Fig. 4B. These data suggest the importance of the therapeutic itself (miR-21-5p) as well as the delivery system (a two-stage delivery) in mitigating the negative LV remodeling and improving the morphology and pumping effectiveness of the heart after MI.

(A) Representative echocardiography imaging by the modified Simpson method of short-axis views for each treatment group at baseline and 45 min, 14 days, and 28 days after MI. The site of the infarct zone is shown by arrows. Notable chamber dilation and wall thinning occurred at 28 days following MI, consistent with the adverse remodeling process. (B) Time course analysis of the EF, LVEDV, LVESV, and LVPWd. (C) MI caused a gradual decline in the EF over 28 days, which was notably attenuated by Gel@MSN/miR-21-5p. (D) MI caused a gradual increase in the LVEDV at day 14 and day 28. The LVEDV of the Gel@MSN/miR-21-5p treatment group was substantially attenuated compared with those of the other three treatment groups. (E) MI caused progressive thinning of the LVPWd thickness at the diastole, which was attenuated by Gel@MSN/miR-NC and agomiR-21-5p treatment and further attenuated by Gel@MSN/miR-21-5p treatment at day 14 and day 28. *P < 0.05 and ***P < 0.01. Sham, n = 3; MI/saline, n = 5; MI/agomir, n = 5; MI/Gel@MSN/miR-NC, n = 6; and MI/Gel@MSN/miR-21-5p, n = 6. The data are shown as the means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Representative delayed-enhancement computed tomography (CT) images of cross-sectional planes of hearts from two-axis (long axis and short axis) slices at day 28 after MI are shown in Fig. 5. The infarct regions in the LV posterior wall were characterized by wall thinning (identified by red counterstain). Analysis of systolic LV wall thickness showed that the wall thickness in the infarcted zone was retained in the agomiR-21-5p and Gel@MSN/miR-NCtreated groups 28 days after MI to a limited degree (marked with white arrows) compared to that in the saline-treated group. LV wall thickness in the infarcted zone was further persevered with the Gel@MSN/miR-21-5ptreated group. Bulls eye plots (Fig. 5A) display LV wall thickness, wall motion, and regional EFs. Global cardiac functional measures such as LVEDV, LVEDV, and EF are shown in the inserted table.

Representative delayed enhancement CT images of cross-sectional planes of hearts from two-axis (long axis and short axis) slices at day 28 after MI are shown. (A) Bulls eye plots display the LV wall thickness, wall motion, and regional EFs. (B) The infarct zone was characterized by wall thinning (identified by white arrows). (C) Global cardiac functional measures such as cardiac output, stroke volume, and EF are shown in the inserted table. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Infarct size as measured by tetraphenyl tetrazolium chloride (TTC) staining also showed that the Gel@MSN/miR-21-5p group had the smallest infarct size (Fig. 6A; paired multiple slices of an infarcted heart in the same pigs shown in fig. S8). The histological characterization of the LV sections from the infarct region at 28 days after MI showed that the infarcted regions in pigs injected with Gel@MSN/miR-21-5p present preserved distinct and thick muscle layers. However, moderately thickened muscle was observed in the agomiR-21-5p and Gel@MSN/miR-NC groups, and obvious fibrillary layers were observed in the saline group. The muscle layers were verified to be cardiomyocytes by anticardiac troponin-T staining (Fig. 6B). Massons trichrome staining showed approximately two times less fibrous content in the Gel@MSN/miR-21-5p group than in the saline group (Fig. 6D). These observations provided evidence that Gel@MSN/miR-21-5p treatment could effectively attenuate fibrosis and improve cardiac remodeling after MI.

A porcine model of MI was used to investigate the post-MI responsiveness of different groups to treatments. Healing at the infarct zone was analyzed after 28 days after treatment. (A) Representative image of TTC-stained hearts and morphometric measures of the infarct area from each group. White coloring in the TTC-stained sections indicates infarct zone and tissue necrosis. (B) Representative histological analysis of the infarcted myocardium among the treatment groups. H&E (left) staining, Massons trichrome staining (middle), and immunohistochemistry staining for cardiac troponin T (right) 28 days after MI showed a loss of cardiomyocytes and collagen deposition, and interstitial fibrosis was substantially reduced in the infarct zone after the Gel@MSN/miR-21-5p treatment (scale bars, 2000 m in the low-magnification images and 60 m in the high-magnification images). Quantitative analysis showing the percentage of the TTC-negative infarct area (C) and fibrotic area (D). (E) miRNA transfection efficiency was investigated using real-time quantitative PCR at 28 days following MI. *P < 0.05 and ***P < 0.01. Sham, n = 3; MI/Saline, n = 5; MI/Agomir, n = 5; MI/Gel@MSN/miR-NC, n = 6; and MI/Gel@MSN/miR-21-5p, n = 6. The data are shown as the mean SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; Shanghai, 200011, China.

The in vivo data relating to drug release duration and efficacy of MSNs and miRNA delivery by Gel@MSN/miR-21-5p were characterized. Confocal images and quantification analysis showed that more than 60% of macrophages (identified by the F4/80+ marker) or endothelial cells (identified by the CD31+ marker) took up the MSN/miR-21-5p complexes 1 day after injection (Fig. 7). Furthermore, the high intracellular transfection efficacy was sustained up to ~28 days, as evidenced by an approximately twofold increase in endogenous miR-21-5p levels (Fig. 7), which could contribute to the improved morphology and pumping effectiveness of the heart.

MSNs were prelabeled with FITC (green), and miR-21-5p was prelabeled with Cy3 (red). The hydrogel (FITC-labeled Gel@MSN/miR-21-5p or Cy3-labeled Gel@MSN/miR-21-5p) was injected into the mid-myocardium of each target site in the pigs. The duration and efficiency of MSNs and miRNA delivery upon Gel@MSN/miR-21-5p injection were monitored using time course analysis at 1, 14, and 28 days after injection. (A) Histological sections of the infarct region in the Gel@MSN/miR-21-5p group were immunolabeled with the hematoxylin and eosin (H&E) macrophage marker F4/80. (B) Histological sections of the infarct region in the Gel@MSN/miR-21-5p group were immunolabeled with the endothelial marker CD31. Cell nuclei were counterstained with DAPI (blue). (C) F4/80+FITC+ and CD31+Cy3+ double-positive cells were quantified from at least eight high-resolution images acquired from at least eight different regions of each heart. (D) miR-21-5p levels were detected using real-time quantitative PCR at different time points. The transfection efficiency was determined by quantifying the miRNA level. Scale bars, 100 m. n = 3 per group. The data are shown as means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

We further compared the effects of MSN/miR-21-5p complexes without a hydrogel matrix (MSN/miR-21-5p alone) and with a hydrogel matrix (Gel@MSN/miR-21-5p) on treating MI. The morphological and functional parameters of the MSN/miR-21-5p group alone were worse than those of the Gel@MSN/miR-21-5p group at 14 and 28 days, and the parameters did not improve over time. The Gel@MSN/miR-21-5p delivery system provided sustained release of miR-21-5p (fig. S9) and sustained a superior therapeutic benefit compared to that from a bolus shot of MSN/miR-21-5p (fig. S10). Histological examination and the quantification of the total infarct size showed similar results. These data suggest that the hydrogel matrix could maintain a long-term drug release, which is important to achieve a persistent therapeutic effect. The hearts were harvested at 28 days after MI for fluorescent imaging, RNA extraction, and real-time quantitative PCR analysis. The fluorescent images showed that the areas of FITC and Cy3 fluorescence enhancement exactly overlapped with the infarct region (Fig. 8A). The confocal images and quantification of miR-21-5p levels showed that MSN/miRNA complexes were effectively transfected into cells within the infarct region in vivo (Fig. 8B). These data indicate that the hydrogel matrix achieved localized sustained drug release, triggered by the acidic microenvironment in the infarct region.

For examination of on-demand delivery, the hearts were harvested at 28 days after MI for fluorescent imaging, RNA extraction, and real-time quantitative PCR analysis. (A) The fluorescent images showed that there were no transfecting cells detected in the sham group. In contrast, it showed that the area of FITC and Cy3 fluorescence exactly overlapped with the infarct region. (B) Quantification of miR-21-5p levels showed that the MSN/miRNA complex could be highly transfected into cells within the infarct region in vivo. Scale bar, 100 m. ***P < 0.01. The data are shown as means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

The three-dimensional (3D) organization of the vascular network within the infarct regions was characterized by micro-CT angiography. The vascular density and volume were significantly improved with Gel@MSN/miR-21-5p (Fig. 9A). CD31 and smooth muscle actin (-SMA) are typical biomarkers of endothelial cells and mural cells in blood vessels. Immunofluorescence characterization showed that expression levels of CD31 and -SMA were significantly enhanced and that more newly formed vessels were observed in the Gel@MSN/miR-21-5p treatment group than in the other groups. These observations provided evidence that Gel@MSN/miR-21-5p treatment enhanced vascularization after MI.

(A) Micro-CT angiography analysis of 3D vascular structures within the infarct zone 28 days after MI indicates that the vascular volume was significantly increased in the Gel@MSN/miR-21-5p treatment group. The vascular volume within the infarct zone was quantitatively analyzed. *P < 0.05 and ***P < 0.01. n = 3 per group. (B) Immunofluorescence staining for CD31 (red) identified the vascular endothelium, and staining for -SMA (green) identified myofibroblasts and pericytes, showing that the cardiac capillary density in histological sections of the healing infarct zone was significantly higher in the Gel@MSN/miR-21-5p treatment group than in the other groups. The CD31 and -SMA staining intensities in the above-described groups were quantitatively analyzed (scale bars, 500 mm). *P < 0.05 and ***P < 0.01. Sham, n = 3; MI/saline, n = 5; MI/agomir, n = 5; MI/Gel@MSN/miR-NC, n = 6; and MI/Gel@MSN/miR-21-5p, n = 6. The data are shown as the means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Immunofluorescence analysis of LV sections taken from the infarct region 1 day after MI showed that Gel@MSN/miR-21-5p effectively protected cardiomyocytes (fig. S11) and inhibited the expression of several key inflammatory mediators (TNF-, IL-1, and IL-6) (Fig. 10). Furthermore, concordant with reduced fibrotic area in the infarcted region in the Gel@MSN/miR-21-5ptreated group at 28 days after MI, the expression of key inflammatory mediators (TNF-, IL-1, and IL-6) was obviously reduced (fig. S12). These results suggested that Gel@MSN/miR-21-5p treatment modulated the immune response after MI by inhibiting the expression of proinflammatory cytokines.

Histological sections of the infarct zone (day 1 after MI) were immunolabeled with antibodies targeting TNF- (A), IL-6 (B), or IL-1 (C) and colabeled with the macrophage marker F4/80 (green). Cell nuclei were counterstained with DAPI (blue). (D) The percentages of cells double positive for F4/80 and TNF-, IL-1, or IL-6 (TNF-, IL-1, or IL-6expressing macrophages, respectively) were quantified. Quantification was performed in at least eight high-resolution images acquired from at least eight different regions of each heart. Scale bars, 100 m. ***P < 0.01. n = 3 per group. The data are shown as the means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

The use of large-animal models of MI provides valuable information regarding the safety and efficacy of new therapies. Pig models offer an alternative because of their anatomical and physiological similarities to humans (40, 41). The treatment groups used materials such as PEG derivatives, CD, silica, and miRNA, and an obvious inflammatory response to foreign bodies was not observed in the treated pigs, indicating its potential for clinical transition.

Here, we report the potential for an efficient miRNA delivery system that simultaneously integrates immune modification and angiogenesis enhancement in the field of MI therapy. This study demonstrates the efficacy and feasibility of a delivery system in a clinically relevant porcine MI model, where both the pathophysiology and the administration mimic what would be observed and performed in humans.

Current therapeutic strategies (angiogenic therapy or anti-inflammatory therapy) involving protein delivery or gene therapy for treating MI have limited success in reducing infarct size (42, 43). The results of our study suggest that therapeutic outcome relies on both immunomodulation and angiogenesis. This study demonstrated that MSNs could reduce the inflammatory responses that can modify tissue remodeling and prevent fibrous tissue formation for improved repair after MI. Specifically, the effect of the resultant microenvironment can be further enhanced with sustained miR-21-5p delivery via MSNs and synergistically stimulate angiogenesis as well as changes in the morphology and pumping effectiveness of the heart after MI.

To date, the study to use miRNA for the treatment of ischemic cardiovascular disease in a preclinical pig model was performed by Gabisonia et al. (22). Gabisonia et al. used miR-199a therapy in an attempt to stimulate cardiomyocyte proliferation. The approach enabled the induction of preexisting cardiomyocytes to reenter the cell cycle and rebuild the injured heart (44). Substantial improvements in cardiac function and structure were attributed to this process. However, there are potential limitations of cardiomyocyte proliferation after birth including cardiomegaly or hypertrophy, as well as possible arrhythmias due to the immaturity of myocyte conduction or poor coupling with existing myocardium (45). As reported by Gabisonia, the generation of areas of poorly differentiated cardiomyocytes might cause tachyarrhythmias and eventually determine fatal reentry electric circuits. The adverse effects were also observed in several other studies, that long-term stimulation of cardiomyocyte proliferation might result in impaired cardiac function or arrhythmic events (4648). In the current study, we attempted to use specific miR-21-5pbased therapies to promote angiogenesis in infarct areas, which may further facilitate rescuing resident cardiomyocytes in an injured heart. We focused on myocardial salvage rather than replacement. The proangiogenic effects of miR-21-5p were characterized with multiple in vitro and in vivo experiments and could be attributed to targeting SPRY1. Loss of SPRY1 leads to the expression of proangiogenic cytokines (VEGFA and PDGF-BB) in endothelial cells. While manipulation of proteins in the Hippo pathway (identified as miR-199a targets) promotes adult cardiomyocyte cell cycling, animals subjected to this type of treatment also exhibit cardiac dysfunction and heart failure in the long term (47, 48). Our strategy represents another direction to promote MI repair. Until now, no major case of arrhythmias has been reported to be associated with long-term proangiogenic therapies in either animal studies or clinical trials. In addition, Gabisonia et al. used adeno-associated virus vectors as therapeutic and investigational tools, which have advantages such as high transfection efficiency. However, such virus-based delivery systems could lead to uncontrollable continuous miR-199a expression and unrestrained cardiac growth in the long term, which would eventually result in sudden death due to arrhythmia at weeks 7 to 8 in most of the treated pigs because controlled miRNA delivery was beyond the current capabilities of virus-mediated gene transfer. Therefore, the treatment needs to be carefully dosed, which could be achieved through the delivery of naked, synthetic miRNA mimics. In our study, a local on-demand and controlled delivery system was described. The system provided a controlled miR-21-5p mimic delivery, with ~75% release over 7 days at pH 6.8 in vitro. In addition, considering the limitation of current RNAi-based therapy associated with potential off-target accumulation, multiple works have been done in this area to optimize the RNAi delivery system (16, 18, 19, 23). For example, a hydrogel system used ultraviolet as the external stimulus to achieve on-demand controlled localized release of RNA at designated time points to induce human mesenchymal stem cell (hMSC) osteogenesis (18, 19). In the present study, the hydrogel is designed to be pH stimuli responsive to achieve on-demand miRNA delivery for persistent and accuracy therapeutic effect on MI. The miRNA delivery system (Gel@MSN/miR-21-5p) specifically released MSN/miR-21-5p only at the infarct region without affecting the surrounding healthy tissues, which addresses the safety issue associated with miRNA-based therapy. As shown in fig. S15, two pigs survived out to 11 months after Gel@MSN/miR-21treatment, and electrocardiography (ECG) was performed. ECG analysis of Q wave and T wave showed that ECG signal at 11 months is similar to that at 4 weeks after Gel@MSN/miR-21 treatment, indicating that Gel@MSN/miR-21 was not likely to pose a long-term safety risk.

Acute inflammation caused by MI is a protective response that kills invading pathogens, should be self-limiting, and leads to healing (49). However, excess activation of the acute inflammatory response leads to cardiac myocyte death. Macrophages play a central role in regulating inflammation. Modulation of macrophage activation may contribute to the resolution of cardiac injury after MI. The results of this study indicate that MSNs can be used to inhibit proinflammatory polarization (M1) in an inflammatory microenvironment following ischemic muscle injury in vivo (50). Gulin-Sarfraz et al. (13) also noticed that empty mesoporous silica particles could reduce the number of neutrophils and down-modulate the inflammatory response in a mouse airway inflammation model. In addition, our data showed that MSNs modulated immune response through down-regulating TLR2, which inhibited the activation of NFB signaling and subsequently decreased the release of proinflammatory cytokines (TNF-, IL-1, and IL-6). Our results are similar to the findings of Lee et al. (51), who demonstrated that exposure to MSNs decreased the expression of proinflammatory cytokines such as TNF-, IL-1, and IL-6 in macrophages. Consistent with these results, a more recent study indicated that MSNs inhibit lymphocyte proliferation, suppress the killing activity of natural killer cells, and decrease proinflammatory cytokine and nitric oxide production in macrophage cells (36).

Previous studies have demonstrated that angiogenesis can be promoted by the fine-tuned delivery of multiple growth factors and cells with biomaterials (52, 53). It relies on the precisely controlled sequential release or direct serial delivery, which are unfavorable for clinical use. The present study has provided a relatively simple approach that shows not only equivalent efficacy in promoting angiogenesis but also a modified cardiac inflammatory response in pigs after MI, suggesting that achieving cardiac repair through the stimulation of angiogenesis in the infarct region with a miRNA (miR-21-5p)based strategy is attainable in large mammals. The vascular volume was significantly improved within the infarct region in pigs treated with Gel@MSN/miR-21-5p. The enhanced vessels within the infarct region were associated with the accumulation of endothelial cells (identified by CD31+) and mural cells (identified by -SMA+) 28 days after MI. The mechanism by which miR-21-5p exerts its cardiac proangiogenic effects in the myocardium was also studied. KEGG analysis suggested that treatment with miR-21-5p complex was positively associated with key angiogenic signaling pathways such as VEGF signaling and PDGF signaling. Multiple experiments were further conducted and concluded that the delivery of miR-21-5p promoted angiogenesis by targeting SPRY1 and subsequently activating VEGF-induced ERK-MAPK signaling. Together, these data suggest that endogenous cardiac repair may be facilitated by the miR-21-5pinduced angiogenic network.

Increasing reports have revealed the advantage and importance of biomaterials in cardiac tissue engineering. Despite the enthusiasm, there are relatively few ongoing clinical trials using injected materials for cardiac repair, perhaps due to a lack of evidence in large-animal studies, which are necessary before progressing to human trials. Pig models offer an alternative because of their anatomical and physiological similarities to humans. The use of a pig model of MI may provide valuable information regarding the safety and efficacy of therapeutic strategies for MI in clinic. We performed a large-animal study with a pig model to demonstrate the translational potential. However, because the immediate treatment after MI may not be relevant to clinical situations, whether this approach also works in chronic cases and whether there exists an optimal therapeutic time window require further evaluation. There are also human-specific issues to consider including PEG immunity and species-specific interactions. Thus, understanding the factors that affect PEG immunity is crucial for both researchers and clinicians to ensure the treatment safety in clinic. Optimization of Gel@MSN/miR-21-5p dose and long-term studies are also needed for clinical translation.

In summary, the two-stage gene delivery system Gel@MSN/miR-21-5p developed in this study consists of three key components, pH-responsive hydrogel matrix, MSNs, and miR-21-5p. The responsive hydrogel serves as a matrix to achieve a highly localized drug release triggered by an acidic microenvironment and a 1-week sustained drug release (first stage release); MSN is the gene transfection vector (second stage release) and itself alone also resolves early inflammation by suppressing the TLR/NFB signaling pathway; and miR-21-5p promotes angiogenesis and mature vessel formation by targeting SPRY1 and subsequently activating VEGF-induced ERK-MAPK signaling. The synergy among these three elements demonstrated significance in treating MI in a swine model via a combination of anti-inflammatory and proangiogenic effects. Clinically relevant positive outcomes were observed upon Gel@MSN/miR-21-5p treatment, such as improved cardiac remodeling, reduced fibrosis formation and infarct size, and increased vascularization. The injectable property of Gel@MSN/miR-21-5p makes it potentially translatable to minimally invasive transcatheter-based surgery. In addition, this study is a proof of concept for controlled gene delivery and can serve as a technological platform to better elucidate the dose-dependent response of genes in MI treatment or deliver any other nucleic acids (such as DNAs, mRNAs, siRNAs, and miRNAs) or treat any other disease.

The purpose of this study was to design a controlled on-demand miR-21-5p delivery system (Gel@MSN/miR-21-5p) using MSNs combined with a hydrogel matrix, simultaneously integrating immune modification and angiogenesis enhancement in the field of MI therapy. Gel@MSN/miR-21-5p was fabricated by embedding MSN/miR-21-5p complexes into an injectable hydrogel matrix. We performed studies to determine the mechanical properties, structure, and on-demand release profile of Gel@MSN/miR-21-5p.

For the in vitro experiment, real-time quantitative PCR, Western blot, and enzyme-linked immunosorbent assay (ELISA) were performed to assess the immunomodulatory effect of MSNs. Real-time quantitative PCR, Western blot, ELISA, and tube formation assays were performed to determine the proangiogenic effect of miR-21-5p. The mechanisms underlying MSN-mediated inflammatory effects and miR-21-5pmediated proangiogenic effects were studied by proteogenomic analysis, real-time quantitative PCR, and Western blot.

For the in vivo experiments, pigs were randomly assigned to treatment groups, and, wherever applicable, treatment conditions were kept blinded until statistical analysis. Group sizes of at least five animals were chosen, which indicated that the therapeutic efficacy and safety of the Gel@MSN/miR-21-5p could be robustly identified. MI was characterized using multiple methods including echocardiography, delayed enhancement CT, TTC staining, and histological examination. The potential cardiac-protective effect against apoptosis induced by ischemia was analyzed by immunofluorescence analysis. The duration and efficiency of MSNs and miRNA delivered by Gel@MSN/miR-21-5p injection were monitored using time course analysis.

Animal protocols related to this study were reviewed and approved by the Institutional Animal Care and Use Committee at the School of Medicine of Shanghai Jiao Tong University. All experiments were performed in accordance with the guidelines published by the Institutional Animal Care and Use Committee at the School of Medicine of Shanghai Jiao Tong University, Shanghai. All animals were obtained from the Ninth Peoples Hospital Animal Center (Shanghai, China).

Yucatan mini pigs (male, 45 to 50 kg) were anesthetized with tiletamine hydrochloride and zolazepam hydrochloride (4 mg/kg). To establish the porcine MI model, transthoracic 2D echocardiographic measurement by Simpsons method (S5-1 transducer, PHILIPS Medical Systems) was performed to ensure that the animal was healthy before instrumentation and MI induction. Following baseline echocardiographic measurements, light anesthesia was maintained by continuous intravenous infusion of propofol (30 to 40 g kg1 min1). ECG, heart rate, and arterial pressure were constantly monitored. The pericardium was opened through a left thoracotomy, and the first two obtuse marginal arteries of the circumflex artery (OM1 and OM2) were identified and ligated to induce MI. Past studies demonstrated that this technique creates a uniform and consistent MI (24). The pericardium was left open. Pigs were randomized to receive a total of six distinct injection of saline, agomiR-21-5p, Gel@MSN/miR-NC, or Gel@MSN/miR-21-5p within a targeted 2 2 cm region of mid-myocardium immediately after MI (six injection sites, 100 l per injection). Sham controls were was processed in an identical fashion with the exception of coronary artery ligation. The injection of each target site is shown in fig. S13. For the Gel@MSN/miR-NC and Gel@MSN/miR-21 treatments, the miR-NC or miR-21 was preloaded in the MSN-NH2-TMA with a mass ratio of 1:10 between miRNA/MSNs. Then, the sterilized aqueous solutions (600 l) containing RNA-loaded MSN-NH2-TMA, CHO-PEG-CHO, and -CD with a mass ratio of 1:5:5 were incubated for 5 min to form an injectable hydrogel precursor with weak interaction, which was further drawn into a separate syringe, and injected into the mid-myocardium to form the final hydrogel at the target site immediately following MI induction. Animals were carefully monitored until they fully recovered from anesthesia.

Pigs were sedated at baseline, and 2D echocardiographic measurements by Simpsons method (IE33 digital ultrasonic scanner, PHILIPS Medical Systems, USA) were performed in right lateral recumbency. Echocardiography measurements were taken before surgery (baseline) and at 45 min, 14 days, and 28 days following MI. Transthoracic echocardiography allowed assessment and further calculation of LV dimensions, cardiac chamber size, wall thicknesses, EF, LVEDV, and LVEDd according to the biplane modified Simpsons rule. For these measurements, standard parasternal long-axis and apical chamber views were obtained.

CT examinations were performed at 28 days after MI. Animals were sedated with a cocktail injection of tiletamine hydrochloride (4 mg/kg) and zolazepam hydrochloride (4 mg/kg) injection. Pigs were placed in a right lateral position.

CT images were acquired with a clinical 320-slice scanner (Aquilion One, TOSHIBA Medical Systems). The heart was scanned along two long-axis views (vertical and horizontal) and with one set of short-axis views covering the entire LV from the atrioventricular valve plane to the apex. The following parameters were used: a tube voltage of 100 kV, a tube current of 75 mA, a gantry rotation time of 330 ms, 0.5-mm section thickness, a resolution of 0.5 0.5 mm, and free breathing. The CT contrast medium (Ultravist 370, Schering) was injected at a flow rate of 3.5 ml/s. To identify the scar and quantify the extent of post-infarction fibrosis, delayed contrast-enhanced multidetector CT images were acquired to assess viability 3 to 5 min after the administration of contrast media for LV function.

Multiphase reconstruction was performed with commercially available software (VITAL, TOSHIBA Medical Systems, Japan) by using short-axis slices from the base of the heart to the apex. The end diastole and end systole were defined as the maximal and minimal LV volume, respectively.

The hearts from each group were harvested, and blood vessels within the heart were imaged by angiography, as previously described (54). Briefly, a 50.8-millimeter, 18-gauge catheter (Surflo Teflon IV Catheter, Terumo Medical, USA) was inserted into the left ventricle of the heart and advanced into the ascending aorta. A 0.9% normal saline solution containing heparin sodium (100 U/ml) was perfused through the vasculature. The vasculature was then fixed by perfusion with 10% neutral buffered formalin (NBF) and cleared with saline. Last, 25 ml of polymerizable, lead chromatebased, radiopaque contrast agent (Microfil MV-122, Flow Tech, USA) was injected using a 30-ml syringe. Samples were stored at 4C for 24 hours to allow polymerization of the contrast agent.

Samples were scanned using micro-CT (Y. Cheetah, YXLON, Germany) with the following settings: 90 kV, 50 A source current, exposure time of 907 ms, and two images every 0.5 of a 360 rotation range at a voxel size of 76 m. 3D reconstruction of the micro-CT image was completed and analyzed using the manufacturers evaluation software (VG studiomax 3.0). The reconstruction was performed using binning mode, providing an isotropic voxel size of 76 m.

Since the infarct area is clearly visible in the heart tissue slice, matching the micro-CT image slices with their corresponding tissue slices could identify the infarct zone within the 3D micro-CT reconstructed model. The sectioning planes of the microtomograph and of the tissue samples are parallel. After sectioning, the infarct areas (infarcted myocardium appears pale) of the heart tissue slices were counterstained in red. After obtaining micro-CT images, the infarct areas of the micro-CT images were identified on the basis of the observation of the tissue slices.

The heart tissue was sectioned starting from the base to the apex. After sectioning, slices were immediately immersed in 2% TTC in 0.9% NaCl at 37C for 30 min for vital staining. Infarcted myocardium appeared pale after TTC staining. The MI area (TTC negative, white) is outlined. The infarcted area and the total area of the LV wall were analyzed using ImageJ software. The infarct size was calculated as follows: counts of TTC-negative area/counts of total LV wall area (%) on short-axial middle LV myocardial slices.

The excised hearts were sectioned through four horizontal planes, and each section was then subdivided into subsections for further histological and molecular analyses, as shown in fig. S14. Briefly, each heart was sectioned into four 1-cm-thick slices, starting from the apex toward the base. Then, two regions (indicated by letters) of each slice were chosen for further histological and molecular analyses. In all quantifications, we considered eight sectors of the four heart sections, and the same regions were chosen in animals with different treatments.

Pig hearts were carefully harvested 28 days following infarction. Samples representing the mid-infarct were sliced. These tissue samples were routinely processed for histologic analysis, and sections (5 m thick) were stained with hematoxylin and eosin (H&E) and Massons trichrome, as previously described (55). Capillary densities were examined by counting the number of capillaries stained with anti-CD31 (ab28364, Abcam, USA) and anti-SMA (ab5694, Abcam, USA) antibodies. For hydrogel immunomodulatory investigation, hearts were collected and processed after 1 and 28 days after MI. Immunofluorescence was used as previously described to identify F4/80+ cells (ab6640, Abcam, USA) colabeling with antiTNF- (ab6671, Abcam, USA), antiIL-6 (ab6672, Abcam, USA), or antiIL-1 antibody (NB600-633, Novas, USA); Alexa Fluor 488labeled donkey anti-rat antibody (Jackson ImmunoResearch Laboratories, USA) and the Alexa Fluor 594labeled anti-rabbit antibody (Jackson ImmunoResearch Laboratories, USA) were used for visualization. Slides were counterstained with DAPI (56). Immunohistochemistry was used to verify cardiomyocytes with anticardiac troponin-T antibody (ab10214). ImageJ software was applied to count blue pixels (positive for collagen) within that region in the trichrome images.

Time course analysis of transfection efficiency of Gel@MSN/miR-21-5p was performed in vivo. MSNs were prelabeled with FITC (green), or miR-21-5p was prelabeled with Cy3 (red). The hydrogel (FITC-labeled Gel@MSN/miR-21-5p or Cy3-labeled Gel@MSN/miR-21-5p) was injected into the mid-myocardium of each target site of pigs. The delivery efficiency of miR-21-5p into endothelial cells was examined by identifying CD31+ cells (ab28364, Abcam, USA) colabeling with Cy3-labeled miR-21-5p. The delivery efficiency of MSNs into macrophages was examined by identifying F4/80+ cells (ab6640, Abcam, USA) colabeled with FITC-labeled MSNs.

To assess whether MSNs could protect against apoptosis in cardiomyocytes, a terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick end labeling assay using an In Situ Cell Death Detection Kit (Roche, Switzerland) was performed at an earlier time (1 day) after MI, which labels broken DNA strands that are often associated with apoptosis. Percentages of positively stained cells were determined by counting the numbers of labeled cells and total cells.

The macrophage activation state was evaluated after intraperitoneal injections of LPS (Sigma-Aldrich, St. Louis, MO; 250 g in 0.5 ml of saline) into mice. Primary peritoneal macrophages were obtained from 20 g of female C57BL6J mice, as previously described (57). Briefly, cell lavage was collected by flushing the peritoneum with cold PBS. The peritoneum was centrifuged (800g, 4C, 9 min), and the pellet was incubated with ACK buffer (Fisher Scientific, Chino, USA) for 1 min to lyse erythrocytes. The remaining cells were cultured in RPMI 1640 medium and 10% fetal bovine serum (FBS) (Gibco, Gaithersburg, USA) at 37C in a 5% CO2 atmosphere and plated to select for adherent macrophages.

Primary cardiomyocytes were obtained from adult C57BL6J mice (8 weeks), as previously described (58). Briefly, the animal is euthanized humanely by cervical dislocation, and the heart is excised, taking care to remove the pericardium. Blood is removed from the coronary vessels after adequate perfusion with EDTA. Next, the heart is perfused with enzyme solution for 8 to 14 min. At the end of the enzyme digestion, the enzyme solution is flushed with 100 M Ca solution for 5 min, after which the heart is excised by dissecting the cannula, atria, and aorta. Once the first digestion was completed, the heart was transferred to a sterile petri dish and a second digestion step is carried out. The ventricular tissue is chopped with small scissors. Fresh digestion buffer was added, and the heart was quickly triturated with fine tweezers and forceps. This second digestion was performed at 37C in an incubator with 5% CO2 for 10 min to facilitate the collagenase activity. The reaction was halted by adding stop buffer containing FBS (Gibco), and the sample was filtered through a 100-m mesh. Following this, cardiomyocytes were purified via gravity separation in a falcon tube for 15 min and washed with Ca solution. After purification, cells were counted in a hemocytometer, seeded in laminin-coated culture dishes, and placed in an incubator with 5% CO2 at 37C.

Endothelial cells were purchased from the cell and stem cell bank (GNO 15, Chinese Academy of Sciences, China) and were maintained in culture with Dulbeccos modified Eagles medium (DMEM) (Gibco) supplied with 10% FBS (BioInd, Israel), as detailed by the manufacturer.

The tube formation assay was performed as previously described (59). Briefly, growth factorreduced Matrigel matrix (Life Technology) was plated in a 24-well plate after thawing at 4C overnight. The plate was then incubated at 37C for 30 min to allow the Matrigel to polymerize. MSNs, MSN/miRNA-NC, and MSN/miRNA-21transfected calcein-labeled endothelial cells in endothelial basal medium 2 (EBM2) supplemented with 0.5% FBS and basic fibroblast growth factor (5 ng/ml) (FGF) final were seeded on the Matrigel-coated well. The plate was then incubated at 37C in a 5% CO2 humidified atmosphere. Tube formation was observed at 8 and 16 hours with confocal microscopy. The tube formation ability was determined by measuring the total tube length of endothelial cells with ImageJ software.

For flow cytometric analyses, cells were blocked with 10% FBS for 10 min on ice and subsequently stained with fluorochrome-tagged anti-F4/80 (BM8, BioLegend) or APC-labeled anti-CD31 (eBioscience, 17-0319-42). All stains were performed in 1% bovine serum albumin PBS buffer for 1 hour in the dark at 4C, followed by two washing steps. Samples were analyzed on a FACSCalibur (BD Biosciences, USA). Dead cells were excluded by forward and side scatter, and data analysis was performed using FlowJo software version 7.6.3 (Tree Star Inc., Ashland, USA).

For in vitro uptake analysis, isolated peritoneal macrophages were cocultured with FITC-labeled nanoparticles (100 g/ml). For in vivo uptake analysis, FITC-labeled Gel@MSN/miR-21-5p was injected into the mid-myocardium of the pigs heart. In vitro and in vivo quantitative uptake of the MSNs by macrophages was determined by quantifying the fluorescence intensity of cells that were positive for F4/80 (ab6640, Abcam, USA) and showed colocalization with FITC.

The growth medium of the hypoxic/ischemia group was replaced with serum-free DMEM. Cells were placed in a hypoxic incubator (Sanyo, O2/CO2 incubator MCO-18M) with oxygen adjusted to 1.0% and CO2 adjusted to 5%. Normal culture (regular medium under 21% oxygen and 5% CO2) served as a control.

The hearts of pigs were collected. Total miRNA from the collected cells or the heart was extracted using the RNeasy Mini Kit (Qiagen) according to the manufacturers instructions. For miRNA level detection, reverse transcription was performed using the Reverse Transcription kit (Takara RR037a, USA) with miRNA-specific stem-loop RT primer (ID: miR8001313, RiboBio, China). Reverse transcriptase reactions contained 0.5 g of RNA samples, 0.2 M stem-loop RT primer, 1 RT buffer, 50 pmol of random primers 6, and PrimerScript Reverse Transcriptase (200 Ul1). The 10-l reactions were incubated in a T100 thermal cycler (Bio-Rad, Hercules, USA) for 15 min at 37C, 5 s at 72C, and then held at 4C. One microliter of cDNA was PCR-amplified using Premix Taq (Takara RR902A) with 1 l of forward primer (0.2 M) and 1 l of reverse primer (0.2 M) for miR-21-5p (RiboBio, ID: miR8001314). The 25-l reaction volume consisted of 1 l of cDNA, 12.5 l of Premix Taq, 9.5 l of ddH2O, 1 l of forward primer (0.2 M), and 1 l of reverse primer (0.2 M). The reactions were performed on a T100 thermal cycler.

The cDNAs were diluted 10 times to perform real-time quantitative PCR using TB Green Premix Ex Taq (Takara RR420A) for miR-21-5p level detection. The 25-l reaction volume consisted of 1 l of cDNA, 12.5 l of Green Premix Ex Taq, 9.5 l of ddH2O, 1 l of forward primer (0.4 M), and 1 l of reverse primer (0.4 M) for miR-21-5p (RiboBio, ID: miR8001314).

For miRNA level detection, cDNAs were synthesized using a reverse transcription kit (Takara, RR037a). Reverse transcriptase reactions contained 0.5 g of RNA samples, 25 pmol of Oligo dT Primer, 1 RT buffer, 50 pmol of random six primers, and PrimerScript Reverse Transcriptase (200 Ul1). The 10-l reactions were incubated in a MyCycler thermal cycler (Bio-Rad, Hercules, CA) for 15 min at 37C and 5 s at 72C and then held at 4C. The cDNAs were then diluted 10 times to perform real-time quantitative PCR for expression confirmation and expression pattern analysis.

The primers used are as follows: -actin (5-CAGGATTCCATACCCAAGAAG-3 and 5-AACCCTAAGGCCAACCGTG-3), IL-1 (5-GAAATGCCACCTTTTGACAGTG-3 and 5-TGGATGCTCTCATCAGGACAG-3), TNF- (5-GACGTGGAACTGGCAGAAGAG-3 and 5-TTGGTGGTTTGTGAGTGTGAG-3), IL-6 (5-TCTATACCACTTCACAAGTCGGA-3 and 5-GAATTGCCATTGCACAACTCTTT-3), TLR1 (5-CCGTCCCAAGTTAGCCCATT-3 and 5-TCCCCCATCGCTGTACCTTA-3), TLR2 (5-TGCGGACTGTTTCCTTCTGA-3 and 5-GCGTTTGCTGAAGAGGACTG-3), TLR3 (5-TACAAAGTTGGGAACGGGGG-3 and 5-GGTTCAGTTGGGCGTTGTTC-3), and TLR8 (5-ACAAACGTTTTACCTTCCTTTGTC-3 and 5-ATGCAGTTGACGATGGTTGC-3).

Western blotting was performed as previously described (56). Total protein was extracted using the EpiQuik whole-cell extraction kit (Epigentek, USA). The protein concentration was measured following the manufacturers instructions (Bio-Rad, USA). Protein was applied to and separated on 4 to 15% NuPAGE gels (Bio-Rad) and transferred to polyvinylidene difluoride membranes (Millipore, USA). The membranes were blocked with 5% bovine serum albumin and incubated with specific primary antibodies against the following: TNF- (AF-410-NA, R&D, USA), IL-1 (Novus, AF-401-NA), IL-6 (bs-0782R, Bioss, USA), VEGFA (DF7470, Affinity, USA), PDGF-BB (bs-1316R, Bioss), TLR1 (NB100-56563, Novus), TLR2 (Abcam, ab209217), TLR3 (NBP2-24875, Novus), TLR8 (NBP2-24917, Novus), NFB (CST8242s, Cell Signaling Technology, USA), p-NFB (CST3033s), SPRY1 (Abcam, ab111523), P-ERK1/2 (AF1018, R&D), ERK1/2 (AF1576, R&D), P-AKT (AF887, R&D), AKT (MAB2055, R&D), P-FAK (MAB4528, R&D), FAK (AF4467, R&D), P-P38 (CST4511), P38 (CST8690), and GAPDH (ab181602) at a ratio of 1:1000 overnight.

Horseradish peroxidaseconjugated IgG (1:10,000 dilution) from Santa Cruz Biotechnology (Santa Cruz, USA) was incubated with the membrane for 1 hour, after which the membranes were enhanced with a SuperSignal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific, USA). The relative amounts of the transferred proteins were quantified by scanning the autoradiographic films. Total protein or nuclear protein was normalized to the corresponding -actin.

For VEGFA and PDGF-BB protein secretion analysis, cells were pretreated with MSN complex loaded with 5 nmol of miR-21-5p as described above. After 6 hours of culture, the medium was replaced with fresh growth medium supplemented with 5.0% serum substitute Nu-Serum (NuS, BD, USA). Samples were collected at 48 hours. VEGFA and PDGF-BB protein levels in the medium were determined using an ELISA according to the manufacturers instructions (R&D Corp., USA). Absorbance was measured at 450 nm with a microplate reader (MTP-800Lab, Corona Electric, Japan). A standard curve was plotted to determine the VEGFA and PDGF-BB concentrations. The values are expressed as picograms per milliliter.

To detect the degradation of Gel@MSN/miR-21 in vivo, the PEG frame of the hydrogel was labeled rhodamine B. Sixty microliters of Gel@MSN/miR-21 was injected into the mid-myocardium of rats after induction of MI. To monitor the residual MSNs in vivo, 60 l of hydrogel containing rhodamine Blabeled MSNs was injected into the mid-myocardium of rats after induction of MI. At the indicated time points, rats were euthanized, and the hearts were removed from the animals. The organs were entirely maintained on ice until ex vivo analysis with Xenogen IVIS imaging system (Alameda, USA). Epifluorescence images of the hearts were acquired. Captured images were then analyzed using the Living Image 4.3.1 software (PerkinElmer Inc., USA). All data obtained by Xenogen IVIS were expressed as radiant efficiency, were assumed to be a calibrated measurement of the photon emission from the subject, and were technically defined as fluorescence emission radiance per incident excitation intensity as follows: photons/s/cm2/sr.

All numerical data are presented as the means SD. Statistical analysis was performed using commercially available software (SPSS 26). Data were first checked for normal distribution, and differences among groups were compared by one-way analysis of variance (ANOVA) followed by the Bonferroni post hoc test. Comparisons between two groups were made using the unpaired t test. For all statistical analyses, significance was accepted at P < 0.05.

Acknowledgments: We thank Y. Zhang and X. Wang (Fudan University) for providing primary cardiomyocytes. The research project was carried out in the Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology. Funding: We acknowledge financial support from the Innovative Research Unit of Chinese Academy of Medical Sciences (2019-12M-5-037) and the National Natural Science Research Program of China (81970977, 31870969, 81870785, 81801039, 81720108011, and 81601606), the Shanghai Municipal Science and Technology Committee research program (number 18DZ2291100), the National Key Research Program of China (2017YFC0840100 and 2017YFC0840109), the Fundamental Research Funds for the Central Universities (2016qngz02), the National Natural Science Foundation of Shaanxi Province (2017JM5023), the Open Fund of the State Key Laboratory of Military Stomatology (2017KA02), and the Knowledge Innovation Program of Shenzhen (JCYJ20170816100941258). Author contributions: Y.L., L.C., D.Z., H.C., and Y.D. carried out animal studies and tissue analyses. X.C. and R.J. carried out the MSN complex synthesis, polyplex development, and Gel@MSN/miR-21-5p hydrogel fabrication and their characterization. Y.L., B.C., J.J.G., G.B., and S.L. contributed to data analysis and interpretation. C.Y., Z.Z., M.D., and Y.L. were responsible for the overall project design and manuscript organization. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Injectable hydrogel with MSNs/microRNA-21-5p delivery enables both immunomodification and enhanced angiogenesis for myocardial infarction therapy in...

Humans are born with a variety of cells. While all of them are absolutely essential for creating us, some cells are more complex and importantlike the nerve cells forming our brain. After all, what is a human body is nothing if not for its brain.

Once the brain cells start to deteriorate, with ageing or injury, humans start to lose cognitive and motor functions. Often seen in cases of Alzheimer's and schizophrenia.

But looking inside a living human brain is impossible; you can only dissect a dead brain that doesnt function. But a group of researchers have overcome this hurdle by building a brain in a dish.

Scientists have been growing living cells in Petri-dishes for a long time. But this research is leaps and bounds ahead as organoids, grown from stem cells, allowed them to conduct extensive genetic analyses. The organoid was allowed to grow for 20 months. They observed it developed in phases, as if on an internal clock, much like the brain of a human infant. This is beyond the former assumption that dish brain could only develop till foetal stage.

Until now, nobody has grown and characterized these organoids for this amount of time, Nor shown they will recapitulate human brain development in a laboratory environment for the most part, said Daniel Geschwind, author of the study. He adds how this will be incredibly useful as models to study the human brain and diseases as the organoids mature and replicate many aspects of normal human development. The study can be found in the journal Nature Neuroscience.

Studying the organoids is helping them understand the physiology and development of diseases like neurological and neurodevelopmental disorders including autism, epilepsy and schizophrenia.

The scientists developed these organoids using pluripotent stem cells. These cells are born one but have the ability to differentiate into multiple specific cells like neurons or cardiac and so on. They induced these cells, derived from skin and blood, to grow into neurons. By manipulating the chemical balance, cell-dish environment and so on, these cells not just developed a rough neural network but self-organised into a structure similar to a 3-D brain.

Excerpt from:
Scientists have Created a 'Brain in a Dish.' It Could Potentially Cure Alzheimer, Dementia - News18

Exosome therapeutic Market Industry Trends and Forecast to 2028 New Research Report Added to Databridgemarketresearch.com database. The report width of pages: 350 Figures: 60 And Tables: 220 in it. Exosome therapeutic Market describes complete industry Outlook with in-depth analysis. This report also includes the complete analysis of each segment in terms of opportunity, market attractiveness index and growth rate, top players and new comers in industry, competitive landscape, sales, price, revenue, gross margin, market share, market risks, opportunities, market barriers, and challenges. key statistics on the market status. Which give the clear idea about the product differentiation and an understanding of competitive landscape Globally.

Exosome therapeutic Market Research report comprises of a brief summary on the trends and tendency that may help the key market players functioning in the industry to understand the market and strategize for his or her Organization expansion for this reason. This statistical surveying report examines the entire market size, market share, key segments, growth, key drivers, CAGR, historic data, present market trends And End User Demand, environment, technological innovation, upcoming technologies and the technical progress in the industry.

Global Exosome Therapeutic Market By Type (Natural Exosomes, Hybrid Exosomes), Source (Dendritic Cells, Mesenchymal Stem Cells, Blood, Milk, Body Fluids, Saliva, Urine Others), Therapy (Immunotherapy, Gene Therapy, Chemotherapy), Transporting Capacity (Bio Macromolecules, Small Molecules), Application (Oncology, Neurology, Metabolic Disorders, Cardiac Disorders, Blood Disorders, Inflammatory Disorders, Gynecology Disorders, Organ Transplantation, Others), Route of administration (Oral, Parenteral), End User (Hospitals, Diagnostic Centers, Research & Academic Institutes), Geography (North America, Europe, Asia-Pacific and Latin America)

Market Analysis and Insights:Global Exosome Therapeutic Market

Exosome therapeutic market is expected to gain market growth in the forecast period of 2019 to 2026. Data Bridge Market Research analyses that the market is growing with a CAGR of 21.9% in the forecast period of 2019 to 2026 and expected to reach USD 31,691.52 million by 2026 from USD 6,500.00 million in 2018. Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

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Exosomes are used to transfer RNA, DNA, and proteins to other cells in the body by making alteration in the function of the target cells. Increasing research activities in exosome therapeutic is augmenting the market growth as demand for exosome therapeutic has increased among healthcare professionals.

Increased number of exosome therapeutics as compared to the past few years will accelerate the market growth. Companies are receiving funding for exosome therapeutic research and clinical trials. For instance, In September 2018, EXOCOBIO has raised USD 27 million in its series B funding. The company has raised USD 46 million as series a funding in April 2017. The series B funding will help the company to set up GMP-compliant exosome industrial facilities to enhance production of exosomes to commercialize in cosmetics and pharmaceutical industry.

Increasing demand for anti-aging therapies will also drive the market. Unmet medical needs such as very few therapeutic are approved by the regulatory authority for the treatment in comparison to the demand in global exosome therapeutics market will hamper the market growth market. Availability of various exosome isolation and purification techniques is further creates new opportunities for exosome therapeutics as they will help company in isolation and purification of exosomes from dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, and urine and from others sources. Such policies support exosome therapeutic market growth in the forecast period to 2019-2026.

This exosome therapeutic market report provides details of market share, new developments, and product pipeline analysis, impact of domestic and localised market players, analyses opportunities in terms of emerging revenue pockets, changes in market regulations, product approvals, strategic decisions, product launches, geographic expansions, and technological innovations in the market. To understand the analysis and the market scenario contact us for anAnalyst Brief, our team will help you create a revenue impact solution to achieve your desired goal.

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Competitive Landscape and Exosome Therapeutic Market Share Analysis

Global exosome therapeutic market competitive landscape provides details by competitor. Details included are company overview, company financials, revenue generated, market potential, investment in research and development, new market initiatives, global presence, production sites and facilities, company strengths and weaknesses, product launch, product trials pipelines, concept cars, product approvals, patents, product width and breadth, application dominance, technology lifeline curve. The above data points provided are only related to the companys focus related to global exosome therapeutic market.

The major players covered in the report are evox THERAPEUTICS, EXOCOBIO, Exopharm, AEGLE Therapeutics, United Therapeutics Corporation, Codiak BioSciences, Jazz Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH, ReNeuron Group plc, Capricor Therapeutics, Avalon Globocare Corp., CREATIVE MEDICAL TECHNOLOGY HOLDINGS INC., Stem Cells Group among other players domestic and global. Exosome therapeutic market share data is available for Global, North America, Europe, Asia-Pacific, and Latin America separately. DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

Many joint ventures and developments are also initiated by the companies worldwide which are also accelerating the global exosome therapeutic market.

For instance,

Partnership, joint ventures and other strategies enhances the company market share with increased coverage and presence. It also provides the benefit for organisation to improve their offering for exosome therapeutics through expanded model range.

Global Exosome Therapeutic Market Scope and Market Size

Global exosome therapeutic market is segmented of the basis of type, source, therapy, transporting capacity, application, route of administration and end user. The growth among segments helps you analyse niche pockets of growth and strategies to approach the market and determine your core application areas and the difference in your target markets.

Based on type, the market is segmented into natural exosomes and hybrid exosomes. Natural exosomes are dominating in the market because natural exosomes are used in various biological and pathological processes as well as natural exosomes has many advantages such as good biocompatibility and reduced clearance rate compare than hybrid exosomes.

Exosome is an extracellular vesicle which is released from cells, particularly from stem cells. Exosome functions as vehicle for particular proteins and genetic information and other cells. Exosome plays a vital role in the rejuvenation and communication of all the cells in our body while not themselves being cells at all. Research has projected that communication between cells is significant in maintenance of healthy cellular terrain. Chronic disease, age, genetic disorders and environmental factors can affect stem cells communication with other cells and can lead to distribution in the healing process. The growth of the global exosome therapeutic market reflects global and country-wide increase in prevalence of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases, along with increasing demand for anti-aging therapies. Additionally major factors expected to contribute in growth of the global exosome therapeutic market in future are emerging therapeutic value of exosome, availability of various exosome isolation and purification techniques, technological advancements in exosome and rising healthcare infrastructure.

Rising demand of exosome therapeutic across the globe as exosome therapeutic is expected to be one of the most prominent therapies for autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases treatment, according to clinical researches exosomes help to processes regulation within the body during treatment of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases. This factor has increased the research activities in exosome therapeutic development around the world for exosome therapeutic. Hence, this factor is leading the clinician and researches to shift towards exosome therapeutic. In the current scenario the exosome therapeutic are highly used in treatment of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases and as anti-aging therapy as it Exosomes has proliferation of fibroblast cells which is significant in maintenance of skin elasticity and strength.

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Exosome therapeutic Market Country Level Analysis

The global exosome therapeutic market is analysed and market size information is provided by country by type, source, therapy, transporting capacity, application, route of administration and end user as referenced above.

The countries covered in the exosome therapeutic market report are U.S. and Mexico in North America, Turkey in Europe, South Korea, Australia, Hong Kong in the Asia-Pacific, Argentina, Colombia, Peru, Chile, Ecuador, Venezuela, Panama, Dominican Republic, El Salvador, Paraguay, Costa Rica, Puerto Rico, Nicaragua, Uruguay as part of Latin America.

Country Level Analysis, By Type

North America dominates the exosome therapeutic market as the U.S. is leader in exosome therapeutic manufacturing as well as research activities required for exosome therapeutics. At present time Stem Cells Group holding shares around 60.00%. In addition global exosomes therapeutics manufacturers like EXOCOBIO, evox THERAPEUTICS and others are intensifying their efforts in China. The Europe region is expected to grow with the highest growth rate in the forecast period of 2019 to 2026 because of increasing research activities in exosome therapeutic by population.

The country section of the report also provides individual market impacting factors and changes in regulation in the market domestically that impacts the current and future trends of the market. Data points such as new sales, replacement sales, country demographics, regulatory acts and import-export tariffs are some of the major pointers used to forecast the market scenario for individual countries. Also, presence and availability of global brands and their challenges faced due to large or scarce competition from local and domestic brands, impact of sales channels are considered while providing forecast analysis of the country data.

Huge Investment by Automakers for Exosome Therapeutics and New Technology Penetration

Global exosome therapeutic market also provides you with detailed market analysis for every country growth in pharma industry with exosome therapeutic sales, impact of technological development in exosome therapeutic and changes in regulatory scenarios with their support for the exosome therapeutic market. The data is available for historic period 2010 to 2017.

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Exosome therapeutic Market Segmentation, Parameters, Prospects 2021 And Forecast Research Report To 2027 KSU | The Sentinel Newspaper - KSU | The...

The Latest Released Autologous Stem Cell Based Therapies market study has evaluated the future growth potential of the Global Autologous Stem Cell Based Therapies Industry and provides information and useful stats on market structure and size. The report is intended to provide market intelligence and strategic insights to help decision-makers take sound investment decisions and identify potential gaps and growth opportunities.

Additionally, the Autologous Stem Cell Based Therapies Market report also identifies and analyses changing dynamics, emerging trends along with essential drivers, challenges, opportunities, and restraints in the Autologous Stem Cell Based Therapies market, which will help the future market to grow with promising CAGR and offers an extensive collection of reports on different markets covering crucial details. The report studies the competitive environment of the Autologous Stem Cell Based Therapies Market is based on company profiles and their efforts on increasing product value and production.

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Keep yourself up to date with the latest market trends and changing dynamics due to COVID Impact and Economic Slowdown globally. Maintain a competitive edge by sizing up with available business opportunities in Autologous Stem Cell Based Therapies Market various segments and emerging territory.

The research offers detailed segmentation of the global Autologous Stem Cell Based Therapies market. Key segments analyzed in the research include Type and Application.

By Type:

By Application:

The report will include a market analysis of Autologous Stem Cell Based Therapies which includes Business to Business (B2B) transactions as well as Autologous Stem Cell Based Therapies aftermarket. The market value has been determined by analyzing the revenue generated by the companies solely. R&D, any third-party channel cost, consulting cost and any other cost except company revenue has been neglected during the analysis of the market. A comprehensive analysis will be provided covering the following points in the report:

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Top Key Players included in Autologous Stem Cell Based Therapies Market:

Region Included are: North America, Europe, Asia Pacific, Oceania, South America, Middle East & AfricaCountry Level Break-Up: United States, Canada, Mexico, Brazil, Argentina, Colombia, Chile, South Africa, Nigeria, Tunisia, Morocco, Germany, United Kingdom (UK), the Netherlands, Spain, Italy, Belgium, Austria, Turkey, Russia, France, Poland, Israel, United Arab Emirates, Qatar, Saudi Arabia, China, Japan, Taiwan, South Korea, Singapore, India, Australia and New Zealand, etc.

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Key questions answered by Autologous Stem Cell Based Therapies market report

Table of Content For Autologous Stem Cell Based Therapies Market Report

Chapter 1. Research Objective

Chapter 2. Executive Summary

Chapter 3. Strategic Analysis

Chapter 4. Autologous Stem Cell Based Therapies Market Dynamics

Chapter 5. Segmentation & Statistics

Chapter 6. Market Use case studies

Chapter 7. KOL Recommendations

Chapter 8. Investment Landscape

Chapter 9. Competitive Intelligence

Chapter 10. Company Profiles

Chapter 11. Appendix

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