Archive for the ‘Bone Marrow Stem Cells’ Category

NEW YORK, Oct. 30, 2020 /PRNewswire/ --Pomerantz LLP announces that a class action lawsuit has been filed against Mesoblast Limited ("Mesoblast" or the "Company") (NASDAQ: MESO) and certain of its officers. The class action, filed in United States District Court for the Southern District of New York, and docketed under 20-cv-09111, is on behalf of a class consisting of all persons other than Defendants who purchased or otherwise, acquired Mesoblast securities between April 16, 2019 and October 1, 2020, inclusive (the "Class Period"). Plaintiff pursues claims against the Defendants under the Securities Exchange Act of 1934 (the "Exchange Act").

If you are a shareholder who purchased Mesoblast securities during the class period, you have until December 7, 2020, to ask the Court to appoint you as Lead Plaintiff for the class. A copy of the Complaint can be obtained at http://www.pomerantzlaw.com. To discuss this action, contact Robert S. Willoughby at [emailprotected]or 888.476.6529 (or 888.4-POMLAW), toll-free, Ext. 7980. Those who inquire by e-mail are encouraged to include their mailing address, telephone number, and the number of shares purchased.

[Click here for information about joining the class action]

Mesoblast develops allogeneic cellular medicines using its proprietary mesenchymal lineage cell therapy platform. Its lead product candidate, RYONCIL (remestemcel-L), is an investigational therapy comprising mesenchymal stem cells derived from bone marrow. In February 2018, the Company announced that remestemcel-L met its primary endpoint in a Phase 3 trial to treat children with steroid refractory ("SR") acute graft versus host disease ("aGVHD").

In early 2020, Mesoblast completed its rolling submission of its Biologics License Application ("BLA") with the U.S. Food and Drug Administration ("FDA") to secure marketing authorization to commercialize remestemcel-L for children with steroid refractory aGVHD.

The complaint alleges that throughout the Class Period, Defendants made materially false and misleading statements regarding the Company's business, operational, and compliance policies. Specifically, Defendants made false and/or misleading statements and/or failed to disclose that: (i) comparative analyses between Mesoblast's Phase 3 trial and three historical studies did not support the effectiveness of remestemcel-L for steroid refractory aGVHD because of design differences between the four studies; (ii) as a result, the FDA was reasonably likely to require further clinical studies; (iii) as a result, the commercialization of remestemcel-L in the U.S. was likely to be delayed; and (iv) as a result of the foregoing, Defendants' positive statements about the Company's business, operations, and prospects were materially misleading and/or lacked a reasonable basis.

On August 11, 2020, the FDA released briefing materials for its Oncologic Drugs Advisory Committee ("ODAC") meeting to be held on August 13, 2020. Therein, the FDA stated that Mesoblast provided post hoc analyses of other studies "to further establish the appropriateness of 45% as the null Day-28 ORR" for its primary endpoint. The briefing materials stated that, because of design differences between these historical studies and Mesoblast's submitted study, "it is unclear that these study results are relevant to the proposed indication."

On this news, the Company's American Depositary Share ("ADS") price fell $6.09 per share, or approximately 35%, to close at $11.33 per share on August 11, 2020, on unusually heavy trading volume.

On October 1, 2020, Mesoblast disclosed that it had received a Complete Response Letter ("CRL") from the FDA regarding its marketing application for remestemcel-L for treatment of SR-aGVHD in pediatric patients. According to the CRL, the FDA recommended that the Company "conduct at least one additional randomized, controlled study in adults and/or children to provide further evidence of the effectiveness of remestemcel-L for SR-aGVHD." The CRL also "identified a need for further scientific rationale to demonstrate the relationship of potency measurements to the product's biologic activity."

On this news, the Company's ADS price fell $6.56 per share, or over 35%, to close at $12.03 per share on October 2, 2020, on unusually heavy trading volume.

The Pomerantz Firm, with offices in New York, Chicago, Los Angeles, and Paris is acknowledged as one of the premier firms in the areas of corporate, securities, and antitrust class litigation. Founded by the late Abraham L. Pomerantz, known as the dean of the class action bar, the Pomerantz Firm pioneered the field of securities class actions. Today, more than 80 years later, the Pomerantz Firm continues in the tradition he established, fighting for the rights of the victims of securities fraud, breaches of fiduciary duty, and corporate misconduct. The Firm has recovered numerous multimillion-dollar damages awards on behalf of class members. See http://www.pomerantzlaw.com.

CONTACT:Robert S. WilloughbyPomerantz LLP[emailprotected]888-476-6529 ext. 7980

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Pomerantz Law Firm Announces the Filing of a Class Action against and Mesoblast Limited Certain Officers - MESO - PRNewswire

The research report on Mesenchymal Stem Cells Market gives thorough insights regarding various key trends that shape the industry expansion with regards to regional perspective and competitive spectrum. Furthermore, the document mentions the challenges and potential restrains along with latent opportunities which may positively impact the market outlook in existing and untapped business spaces. Moreover, it presents the case studies, including the ones related to COVID-19 pandemic, to convey better understanding of the industry to all the interested parties.

The recent market trend of increasingly using Mesenchymal Stem Cells for understanding the development of a disease extensively fuel the growth of this market in the coming years. Another trend that will aid the growth of the global Mesenchymal Stem Cells market is the escalating demand for personalized medicine. Extensive investments are being made by various organizations, pharmaceutical companies, and governments for the research and development of drugs, and this is another trend that is benefiting the growth of the global Mesenchymal Stem Cells market. This is because Mesenchymal Stem Cells techniques enable researchers to compare Mesenchymal Stem Cells changes between disease samples and normal samples. Public health can thus be analyzed as the changes in Mesenchymal Stem Cells are influenced by internal biological system and environment directly.

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The report covers extensive analysis of the key market players in the market, along with their business overview, expansion plans, and strategies. The key players studied in the report include: Advanced Cell Technology Incorporated, Stem cell technologies Inc., Stemedica Cell Technologies, Inc., Cyagen Biosciences Inc., EMD Millipore Corporation, ScienCell Research Laboratories., Cytori Therapeutics Inc., Cell Applications, Inc., Axol Bioscience Ltd., Aastrom Biosciences, BrainStorm Cell Therapeutics., R&D Systems, Inc., Genlantis, Inc., Celprogen, Inc..

Mesenchymal Stem Cells Market Segmentation:

In market segmentation by types of Mesenchymal Stem Cells, the report covers-

Bone MarrowUmbilical Cord BloodPeripheral BloodLung TissueSynovial TissuesAmniotic FluidsAdipose Tissues

In market segmentation by applications of the Mesenchymal Stem Cells, the report covers the following uses-

InjuriesDrug DiscoveryCardiovascular InfractionOthers

Regional Analysis for Mesenchymal Stem Cells Market-:

1) North America- (United States, Canada)

2) Europe- (Germany, France, UK, Italy, Russia, Spain, Netherlands, Switzerland, Belgium)

3) Asia Pacific- (China, Japan, Korea, India, Australia, Indonesia, Thailand, Philippines, Vietnam)

4) Middle East & Africa- (Turkey, Saudi Arabia, United Arab Emirates, South Africa, Israel, Egypt, Nigeria)

5) Latin America- (Brazil, Mexico, Argentina, Colombia, Chile, Peru)

The report provides insights on the following pointers :

Market Penetration: Comprehensive information on the product portfolios of the top players in the Supply Chain Analytics market.

Product Development/Innovation: Detailed insights on the upcoming technologies, R&D activities, and product launches in the market

Competitive Assessment: In-depth assessment of the market strategies, geographic and business segments of the leading players in the market

Market Development: Comprehensive information about emerging markets. This report analyzes the market for various segments across geographies

Market Diversification: Exhaustive information about new products, untapped geographies, recent developments, and investments in the Supply Chain Analytics market

NOTE: Our analysis involves the study of the market taking into consideration the impact of the COVID-19 pandemic. Please get in touch with us to get your hands on an exhaustive coverage of the impact of the current situation on the market. Our expert team of analysts will provide as per report customized to your requirement.

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Table of Content

Chapter 1 Mesenchymal Stem Cells Introduction and Market Overview

Chapter 2 Executive Summary

Chapter 3 Industry Chain Analysis

Chapter 4 Global Mesenchymal Stem Cells Market, by Type

Chapter 5 Mesenchymal Stem Cells Market, by Application

Chapter 6 Global Mesenchymal Stem Cells Market Analysis by Regions

Chapter 7 North America Mesenchymal Stem Cells Market Analysis by Countries

Chapter 8 Europe Mesenchymal Stem Cells Market Analysis by Countries

Chapter 9 Asia Pacific Mesenchymal Stem Cells Market Analysis by Countries

Chapter 10 Middle East and Africa Mesenchymal Stem Cells Market Analysis by Countries

Chapter 11 South America Mesenchymal Stem Cells Market Analysis by Countries

Chapter 12 Competitive Landscape

Chapter 13 Industry Outlook

Chapter 14 Global Mesenchymal Stem Cells Market Forecast

Chapter 15 New Project Feasibility Analysis

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Mesenchymal Stem Cells Market Augmented Expansion to Be Registered by 2020-2025 - Eurowire

What is Adipose Tissue Derived Stem Cell Therapy?

Adipose tissue derived stem cells (ADSCs) are stem cells originated from adipocytes. ADSCs have characteristics similar to bone marrow mesenchymal stem cells. Thus Adipose-derived stem cells substitute for bone marrow as a source of stem cells. Different varieties of manual and automatic stem cell separation procedures are used to separate adipose stem cells (ASCs) from adipose tissue. Flow cytometry can be utilized to isolate ADSCs from other stem cells within a cell solution. Currently, adipose derived stem cells (ADSCs) are generally used in the generation of regenerative medicine due to its anti-inflammatory, anti-apoptotic, and immunomodulatory properties.

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A new market study report by The Insight Partners on the Adipose Tissue Derived Stem Cell Therapy Market has been released with reliable information and accurate forecasts for a better understanding of the current and future market scenarios. The report offers an in-depth analysis of the global market, including qualitative and quantitative insights, historical data, and estimated projections about the market size and share in the forecast period. The forecasts mentioned in the report have been acquired by using proven research assumptions and methodologies. Hence, this research study serves as an important depository of the information for every market landscape. The report is segmented on the basis of types, end-users, applications, and regional markets. Some of the key players in the study are AlloCure, Inc, Antria, Inc., Celgene Corporation, Cellleris SA, Corestem, Inc., Cytori Therapeutics, LLC, Intrexon, Inc., Mesoblast Ltd., Pluristem Therapeutics, Inc., Tissue Genesis, Inc. etc.

Market Insights:

The Adipose Tissue-derived Stem Cell Therapy Market is growing due to increasing use of regenerative medicine in disease treatment and increasing private and public funding for stem cell therapy. However, high cost associated with stem cell processing hampers growth of this market.

An Overview of the Impact of COVID-19 on this Market:

Due to the pandemic, we have included a special section on the Impact of COVID 19 on the Adipose Tissue Derived Stem Cell Therapy Market which would mention How the Covid-19 is Affecting the Adipose Tissue Derived Stem Cell Therapy Industry, Market Trends and Potential Opportunities in the COVID-19 Landscape, Covid-19 Impact on Key Regions and Proposal for Adipose Tissue Derived Stem Cell Therapy Players to fight Covid-19 Impact.

Adipose Tissue Derived Stem Cell Therapy Market: Regional analysis includes:

The Adipose Tissue Derived Stem Cell Therapy Market segments and Market Data Break Down are illuminated below:By Cell Type (Autologous Stem Cells, Allogeneic Stem Cells);

Product (Cell Line, Culture Media);

Disease (Cancer, Obesity, Wounds and Injuries, Musculoskeletal Diseases, Cardiovascular Diseases, Others);

End User (Hospitals and Trauma Centers, Cell banks and Tissue Banks, Research Laboratories and Academic Institutes, Others)

The study conducts SWOT analysis to evaluate strengths and weaknesses of the key players in the Adipose Tissue Derived Stem Cell Therapy market. Further, the report conducts an intricate examination of drivers and restraints operating in the market. The report also evaluates the trends observed in the parent market, along with the macro-economic indicators, prevailing factors, and market appeal with regard to different segments. The report predicts the influence of different industry aspects on the Adipose Tissue Derived Stem Cell Therapy market segments and regions.

This report strategically examines the micro-markets and sheds light on the impact of technology upgrades on the performance of the Adipose Tissue Derived Stem Cell Therapy market.

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Adipose Tissue Derived Stem Cell Therapy Market to Set Phenomenal Growth in Key Regions by 2027 | AlloCure, Inc, Antria, Inc., Cellleris SA, Tissue...

Transparency Market Research (TMR) has published a new report titled, Cord Blood Banking Services Market Global Industry Analysis, Size, Share, Growth, Trends, and Forecast, 20192027. According to the report, the global cord blood banking services market was valued at US$ 25.8 Mn in 2018 and is projected to expand at a CAGR of 10.9% from 2019 to 2027.

Overview

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High Incidence of genetic disorders and rise in hematopoietic stem cell transplantation rates to Drive Market

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Private Cord Blood Bank Segment to Dominate Market

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North America to Dominate Global Market

Competitive Landscape

The global cord blood bank services market is fragmented in terms of number of players. Key players in the global market include Global Cord Blood Corporation, California Cryobank Stem Cell Services LLC, Inc., CBR Systems, Inc., Cordlife Group Limited, Cryo Cell International, Inc., Cryo-Save AG, Lifeforce Cryobanks, National Cord Blood Program, ViaCord, Inc., Virgin Health Bank among others.

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Cord Blood Banking Services Market is Anticipated to Expand at a CAGR of 10.9% from 2019 to 2027 - The Think Curiouser

The Global Hematopoietic Stem Cell Transplantation (HSCT) Market report offers key insights into the worldwide Hematopoietic Stem Cell Transplantation (HSCT) market. It presents a holistic overview of the market, with an in-depth summary of the markets leading players. The report is inclusive of indispensable information related to the leading competitors in this business sector and carefully analyzes the micro- and macro-economic market trends. The latest report specializes in studying primary and secondary market drivers, market share, the leading market segments, and comprehensive geographical analysis. Vital information about the key market players and their key business strategies, such as mergers & acquisitions, collaborations, technological innovation, and trending business policies, is one of the key components of the report.

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The report covers extensive analysis of the key market players in the market, along with their business overview, expansion plans, and strategies. The key players studied in the report include:

China Cord Blood Corp, Pluristem Therapeutics Inc., CBR Systems Inc CellGenix Technologie Transfer GmbH, Cryo-Save AG Kite Pharma Inc., Regen Biopharma Inc., ViaCord Inc., BiolineRx, Cynata Therapeutics, Cesca Therapeutics Inc, Lonza Group Ltd, TiGenix N.V., Bluebird Bio, Cellular Dynamics International, and Escape Therapeutics Inc., among others.

Furthermore, our market analysts have drawn focus to the significant impact of the COVID-19 pandemic on the global Hematopoietic Stem Cell Transplantation (HSCT) market and its key segments and sub-segments. The grave aftereffects of the pandemic on the global economy, and subsequently, on this particular business sphere, have been enumerated in this section of the report. The report considers the key market-influencing parameters, delivering a detailed future impact assessment. The Hematopoietic Stem Cell Transplantation (HSCT) market has been devastated by the pandemic, which has culminated in drastic changes to the market dynamics and demand trends.

In market segmentation by types of Hematopoietic Stem Cell Transplantation (HSCT), the report covers-

In market segmentation by applications of the Hematopoietic Stem Cell Transplantation (HSCT), the report covers the following uses-

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Moreover, the research report thoroughly examines the size, share, and market volume of the Hematopoietic Stem Cell Transplantation (HSCT) industry in the historical years to forecast the same valuations over the forecast duration. It offers exhaustive SWOT analysis, Porters Five Forces analysis, feasibility analysis, and investment return analysis of the Hematopoietic Stem Cell Transplantation (HSCT) market, assessed using certain effective analytical tools. The report also provides strategic recommendations to market entrants to help them navigate around the entry-level barriers.

The global Hematopoietic Stem Cell Transplantation (HSCT) market is geographically categorized into:

The following timeline is considered for market estimation:

Historical Years: 2017-2018

Base Year: 2019

Estimated Year: 2020

Forecast Years: 2020-2027

Key Coverage of the Report:

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After tackling two major research challenges, the founders of Be Biopharma are ready to announce their official launch along with a $52 million funding round. They are intent upon usingthe bodys B cells to treat a range of diseases.

The Series A round was led by Atlas Venture and RA Capital Management. Joining in were Longwood, Alta Partners and Takeda Ventures.

We have an ambitious plan to be the company that knows how to make B cells and mirror them precisely and make them at scale, Aleks Radovic-Moreno, Be Biopharmas president and director, said in a phone interview.

B cells, which play a leading role in the bodys immune response, can be taken out, genetically programmed to help fight specific diseases and then put back in the body. The cells also can come from healthy donors.

The challenges involved being able to efficiently edit the cells and then make them in sufficient quantities, Radovic-Moreno said. Those are the two big problems we have overcome.

Founded this year, Be Biopharma is looking to hire people in research, engineering and manufacturing, as well as a full-time leadership team, said Radovic-Moreno, an entrepreneur in residence at Longwood Fund, a co-founder and investor in Be Biopharma. The startups CEO is David Steinberg, a general partner at Boston-based Longwood.

From there, the company hopes to begin developing therapeutics for use in people. Cancers and autoimmune diseases are potential targets, as are monogenic diseases like cystic fibrosis. B cells, for example, could replace the need for invasive bone marrow transplants, Radovic-Moreno said.

If we can do that, it would change the lives of so many people. So, were trying to move that as fast as humanly possible, said Radovic-Moreno, who declined to offer a specific timeline.

The path for B cells could be relatively quick, he said, based on the experience of T cells and stem cells, he said. B cell therapies, though, are expected to be safer and less toxic than those involving T cells.

Be Biopharma is drawing on research undertaken at the Seattle Childrens Research Institute by Dr. David Rawlings and Richard James. They are among the co-founders of the new company.

B cells play a key role in combatting diseases by catalyzing humoral immunity the arm of the immune system that manufactures large quantities of proteins to neutralize disease-causing pathogens and manipulate immune cell behavior, Rawlings, director of the Center for Immunity and Immunotherapies at the Seattle institute, said in a statement. Today, this powerful part of the immune system is only passively and/or indirectly addressed therapeutically. Our ambition is to advance the field by building a new class of engineered B cell medicines that will provide direct control over the power of humoral immunity and help transform the prognosis for patients who currently have limited treatment options.

Picture: Feodora Chiosea, Getty Images

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Startup focused on B-cell therapies launched with $52M in Series A - MedCity News

Prophecy Market Insights has recently published the Stem Cell Therapy informational report which evaluates market size, growth rate, profit margin, raw material availability, impact strength, competition, technology, and environmental and legal factors.

The report covers all recent trends, opportunities, drivers, and restraints of the Stem Cell Therapy market coupled with their impact on demand over the forecast period. Additionally, the report provides a comprehensive view of the market by offering exhaustive value chain analysis. It provides in-depth information about value addition at each stage of the value chain.

Comprehensive information pertaining to fire alarm systems and its properties is provided in this section. This section also highlights the inclusions and exclusions, which help readers to understand the scope of the market report.

This segment includes factors that have emerged as key successful factors and strategies adopted by key market participants.

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The Stem Cell Therapy market report provides a detailed analysis of market players according to its production footprint, market share, and growth rate. The report also covers SWOT analysis (strengths, weaknesses, opportunities, and threats) of the players. Besides, the Stem Cell Therapy market study depicts the recent launches, R&D projects, agreements, and business strategies of the market players including market segmentation and regional analysis of the market.

The Stem Cell Therapy market study covers both the top-down and bottom-up approaches that have been used to calculate and authenticate the market size and estimate the scenario of various sub-markets in the global market. The report estimation size of the market both in terms of volume (x units) and value (Mn/Bn USD).

Stem Cell Therapy Market by Top Manufacturers:

Scope of the Market Research Report:

The report takes into account the impact of the novel COVID-19 pandemic on the market and provides a clear assessment of the estimated market fluctuations throughout the forecast period.

Important Questions Answered in Stem Cell Therapy Market Report:

Segmentation Overview:

Global Stem Cell Therapy Market, By Treatment Type:

Global Stem Cell Therapy Market, By Cell Source:

Global Stem Cell Therapy Market, By Indication:

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Provides recent collaborations, mergers, acquisitions, and partnerships along with regulatory framework across vast regions impacting the market trajectory

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Stem Cell Therapy Market: Applications and Regional Insights During the Forecasted Period 2020-2030 - PRnews Leader

Tel Aviv, Israel , Oct. 29, 2020 (GLOBE NEWSWIRE) -- Adding to a growing roster of partners, Cellect Biotechnology Ltd. (NASDAQ: "APOP"), announced that it has entered into and commenced a collaborative development program with Sweden-based XNK Therapeutics, a pioneer in natural killer (NK) cell-based therapies.

This latest agreement demonstrates the continued progress and operational momentum we are continuing to generate, further validating our strategic vision and potential revenue opportunities, commented Dr. Shai Yarkoni, Chief Executive Officer. We join an already prestigious group of organizations that are currently collaborating with XNK Therapeutics, including the Karolinska Institute and the Royal Institute of Technology, and we are looking forward to fostering a long-term business and commercial collaboration. We remain focused on commercializing our functional cell selection technology so patients and markets can benefit from the proven safety profile and better outcomes of a broad range of cell and gene therapies.

Under the terms of the agreement, Cellect will help improve XNK Therapeutics technology platform, for targeting cancer across a wide range of indications. Cellect expects to expand the business arrangement based on the outcomes of the ongoing studies at XNK Therapeutics. Cellects functional cell selection technology has the potential to significantly improve the consistency and manufacturing efficiency in autologous as well as future allogeneic transplantation

XNK Therapeutics is expected to leverage Cellects simple, safe and inexpensive process as part of its efforts to create the next generation version of its innovative therapy platform. I am excited that we continue developing the next generation of XNK Therapeutics technology platform and looking forward to the collaboration with Cellect says Johan Liwing CEO of XNK Therapeutics.

About Cellect Biotechnology Ltd.

Cellect Biotechnology (APOP) has developed a breakthrough technology, for the selection of stem cells from any given tissue, that aims to improve a variety of stem cell-based therapies.

Story continues

The Company's technology is expected to provide researchers, clinical community and pharma companies with the tools to rapidly isolate stem cells in quantity and quality allowing stem cell-based treatments and procedures in a wide variety of applications in regenerative medicine. The Company's current clinical trial is aimed at bone marrow transplantations in cancer treatment.

Forward Looking Statements

This press release contains forward-looking statements about the Company's expectations, beliefs and intentions. Forward-looking statements can be identified by the use of forward-looking words such as "believe", "expect", "intend", "plan", "may", "should", "could", "might", "seek", "target", "will", "project", "forecast", "continue" or "anticipate" or their negatives or variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical matters. For example, forward-looking statements are used in this press release when we discuss Cellect's expectations regarding timing of the commencement of its planned U.S. clinical trial and its plan to reduce operating costs. These forward-looking statements and their implications are based on the current expectations of the management of the Company only and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. In addition, historical results or conclusions from scientific research and clinical studies do not guarantee that future results would suggest similar conclusions or that historical results referred to herein would be interpreted similarly in light of additional research or otherwise. The following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: the Company's history of losses and needs for additional capital to fund its operations and its inability to obtain additional capital on acceptable terms, or at all; the Company's ability to continue as a going concern; uncertainties of cash flows and inability to meet working capital needs; the Company's ability to obtain regulatory approvals; the Company's ability to obtain favorable pre-clinical and clinical trial results; the Company's technology may not be validated and its methods may not be accepted by the scientific community; difficulties enrolling patients in the Company's clinical trials; the ability to timely source adequate supply of FasL; risks resulting from unforeseen side effects; the Company's ability to establish and maintain strategic partnerships and other corporate collaborations; the scope of protection the Company is able to establish and maintain for intellectual property rights and its ability to operate its business without infringing the intellectual property rights of others; competitive companies, technologies and the Company's industry; unforeseen scientific difficulties may develop with the Company's technology; the Company's ability to retain or attract key employees whose knowledge is essential to the development of its products; and the Companys ability to pursue any strategic transaction or that any transaction, if pursued, will be completed. Any forward-looking statement in this press release speaks only as of the date of this press release. The Company undertakes no obligation to publicly update or review any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by any applicable securities laws. More detailed information about the risks and uncertainties affecting the Company is contained under the heading "Risk Factors" in Cellect Biotechnology Ltd.'s Annual Report on Form 20-F for the fiscal year ended December 31, 2019 filed with the U.S. Securities and Exchange Commission, or SEC, which is available on the SEC's website, http://www.sec.gov, and in the Company's periodic filings with the SEC.

ContactCellect Biotechnology Ltd.Eyal Leibovitz, Chief Financial Officerwww.cellect.co+972-9-974-1444

Or

EVC Group LLC Michael Polyviou(732) 933-2754mpolyviou@evcgroup.com

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Cellect Biotechnology Commences Collaboration with XNK Therapeutics to Advance Novel NK Cell-Based Therapies; Adds Another Partner for its Functional...

Careful, man, theres a beloved actor here.

Jeff Bridges revealed that he has lymphoma, which is the most common type of blood cancer. And this sobering news has spurred celebrities and fans to send their best wishes to the star best known for playing the Dude, the White Russiandrinking bowler and casual-wear icon from the Coen brothers 1998 cult classic, The Big Lebowski.

But the Dude abides, and Bridges suggested that his outlook looks just as promising.

As the Dude would say.. New S**T has come to light, tweeted Bridges, 70, on Monday. I have been diagnosed with Lymphoma. Although it is a serious disease, I feel fortunate that I have a great team of doctors and the prognosis is good.

Celebrities such as Cary Elwes, John Lithgow, Patricia Arquette and George Takei posted encouraging words and prayers to Bridges, who is the son of Lloyd and Dorothy Bridges, and has starred in more than 70 films including Starman, True Grit and The Last Picture Show. He won an Academy Award in 2010 for Crazy Heart, and was honored with the Cecil B. DeMille lifetime-achievement award during the 2019 Golden Globes.

And he is now one of the most high-profile cases of lymphoma, a cancer of the bodys infection-fighting lymphatic system that affects the blood and bone marrow. And more than 85,000 new cases of lymphoma are expected to be diagnosed in the U.S. this year, according to American Cancer Society data shared by the Leukemia & Lymphoma Society, with some 791,550 people currently living with lymphoma or in remission from the disease in the U.S.

Many different types of lymphoma exist, and Bridges did not share any more details about his diagnosis or treatment. But his disclosure is an opportunity to share more information about lymphoma, the risk factors and symptoms to be aware of, as well as treatment options.

What is lymphoma?

Lymphoma is a type of cancer that starts in cells that are part of the bodys immune system, specifically the lymphocytes, which are a type of white blood cell that fights germs. So these cancers can affect the blood and bone marrow, as well as the other tissues and organs that produce, store and carry white blood cells including the spleen.

Doctors still dont know what specifically causes lymphoma, but at some point a lymphocyte mutates and begins to reproduce rapidly. The mutated, abnormal cells live longer than the normal cells would, and in time, the diseased and ineffective lymphocytes outnumber the healthy cells, which causes the lymph nodes, liver and spleen to swell.

There are two main types of lymphoma, the CDC explains, including:

Hodgkin lymphoma (HL), which spreads in an orderly manner from one group of lymph nodes to another.

Non-Hodgkin lymphoma (NHL), which spreads through the lymphatic system in a non-orderly manner.

What are the symptoms?

Signs and symptoms of lymphoma may include:

These symptoms can be signs of other health conditions, of course, so its recommended that anyone experiencing them should see a doctor to determine the cause.

How is it treated?

There are many different types of lymphoma including 90 different types of non-Hodgkin lymphoma and treatment varies depending on the type and severity. Generally, lymphoma treatment involves chemotherapy, radiation therapy and immunotherapy medication. The Mayo Clinic, which is an international authority on lymphoma research, explains that the goal of treatment is to destroy as many cancer cells as possible to bring the disease into remission. A bone marrow or stem cell transplant may be performed in some cases to help rebuild healthy bone marrow after chemo and radiation has suppressed the diseased bone marrow.

Bridges didnt specify his own treatment, only saying that he is beginning treatment and will keep the public posted on his recovery.

Treatment can be very expensive, however, with almost 60% of patients covered by Medicare telling the Leukemia & Lymphoma Society in a 2019 study that they decided to delay or forego treatment, largely due to steep out-of-pocket costs. It noted that some traditional Medicare lymphoma patients getting anti-cancer therapy though infusions experienced out-of-pocket costs of more than $19,000 in their first year. And costs can extend two or three years beyond a blood cancer diagnosis.

Who is most at risk?

While children, teens and adults can all develop lymphoma, some types are more common in certain age groups. The CDC notes that rates of Hodgkin lymphoma are highest among teens and young adults (ages 15 to 39) as well as among older adults (ages 75 and older). But non-Hodgkin lymphoma becomes more common as people get older.

Men are also slightly more likely to develop lymphoma than women, the CDC adds, and white people are more likely than Black people to develop non-Hodgkin lymphoma.

Cases have also been more common in people who are immunocompromised, including those who take drugs to suppress their immune systems. And some infections such as HIV and the Epstein-Barr virus are also associated with an increased lymphoma risk.

And like many other cancers, family history has been linked with a higher risk of Hodgkin lymphoma.

What is the survival rate?

The good news is, Hodgkin lymphoma is now considered to be one of the most curable forms of cancer, according to the Leukemia & Lymphoma Society, with a five-year survival rate of 94.4% among patients younger than 45 at diagnosis. And the five-year relative survival rate for those with Hodgkin lymphoma more than doubled from 40% in whites in 1960 to 1963 (the only data available) to 88.5% for all races from 2009 to 2015.

And the five-year relative survival rate for people with non-Hodgkin lymphoma rose from 31% in whites from 1960 to 1963 (the only data available) to 74.7% for all races from 2009 to 2015.

Still, an estimated 20,910 Americans are expected to die from lymphoma this year, including 19,940 with non-Hodgkin lymphoma and 970 with Hodgkin lymphoma.

How does COVID-19 complicate things?

While the medical community is still learning about COVID-19, the general consensus is that people with cancer, who are in active cancer treatment or have previously been treated for cancer, may be at higher risk of severe illness and death if they get the coronavirus. So its important that these folks lower their risk of exposure to COVID-19 by avoiding large crowds and non-essential travel; working from home, if possible; staying at least six feet away from people outside their household; wearing a face mask when they cant socially distance; as well as washing their hands frequently, and not touching their eyes, nose or mouth.

Where can I find more information or support?

Visit the CDC and American Cancer Society pages on lymphoma.

The Mayo Clinic also outlines its lymphoma research and treatment strategies on its website.

The Leukemia & Lymphoma Society and the Lymphoma Research Foundation also provide valuable information and support.

Read more:
Jeff Bridges is one of the 85,000-plus lymphoma cases expected in the U.S. this year - MarketWatch

The report on Global Orthopedic Regenerative Medicine Market is a dependable point of reference heralding high accuracy business decisions on the basis of thorough research and observation by seasoned research professionals at CMI Research. The report on global Orthopedic Regenerative Medicine market evidently highlights the causal factors such as demand analysis, trend examination, and technological milestones besides manufacturing activities that have been systematically touched upon to instigate systematic growth projection.

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Which market players and aspiring new entrants may witness seamless entry?

Curasan, Inc., Carmell Therapeutics Corporation, Anika Therapeutics, Inc., Conatus Pharmaceuticals Inc., Histogen Inc., Royal Biologics, Ortho Regenerative Technologies, Inc., Swiss Biomed Orthopaedics AG, Osiris Therapeutics, Inc., and Octane Medical Inc.

Predicting Scope: Global Orthopedic Regenerative Medicine Market, 2020-2027

Elaborate research proposes global Orthopedic Regenerative Medicine market is likely to experience an impressive growth through the forecast span, 2020-2027, ticking a robust CAGR of xx% USD. The Orthopedic Regenerative Medicine market is anticipated to demonstrate a whopping growth with impressive CAGR valuation. The Orthopedic Regenerative Medicine market is also likely to maintain the growth spurt showing signs of steady recovery.

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Segmentation Based on Orthopedic Regenerative Medicine Market Types:

By Procedure Cell TherapyTissue EngineeringBy Cell TypeInduced Pluripotent Stem Cells (iPSCs)Adult Stem CellsTissue Specific Progenitor Stem Cells (TSPSCs),Mesenchymal Stem Cells (MSCs)Umbilical Cord Stem Cells (UCSCs)Bone Marrow Stem Cells (BMSCs)By SourceBone MarrowUmbilical Cord BloodAdipose TissueAllograftsAmniotic FluidBy ApplicationsTendons RepairCartilage RepairBone RepairLigament RepairSpine RepairOthers

Global Orthopedic Regenerative Medicine Market Size & Share, By Regions and Countries/Sub-regions:

Asia Pacific: China, Japan, India, and Rest of Asia Pacific

Europe: Germany, the UK, France, and Rest of Europe

North America: the US, Mexico, and Canada

Latin America: Brazil and Rest of Latin America

Middle East & Africa: GCC Countries and Rest of Middle East & Africa

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Here is the original post:
Covid-19 Impact On Orthopedic Regenerative Medicine Market 2020 Future Development, Manufacturers, Trends, Share, Size And Forecast to 2027 |...

This article was originally published here

N Engl J Med. 2020 Oct 27. doi: 10.1056/NEJMoa2026834. Online ahead of print.

ABSTRACT

BACKGROUND: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.

METHODS: We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.

RESULTS: We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweets syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.

CONCLUSIONS: Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).

PMID:33108101 | DOI:10.1056/NEJMoa2026834

See original here:
Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease - DocWire News

A one-year-old girl donated her bone marrow to her brother. (Representational)

A one-year-old girl, conceived by her parents through IVF technology specifically for the purpose of donating her bone marrow to their thalassemic son, has succeeded in saving her six-year-old brother's life.

Baby Kavya was born a year ago through In-Vitro Fertilisation (IVF) technique in Ahmedabad, under the concept known as "saviour sibling".

Her bone marrow was successfully transplanted to her brother Abhijeet Solanki in March this year and the boy is now "risk-free", doctors said on Thursday.

Abhijeet, the second child of Sahdev Singh Solanki and Alpa Solanki, was diagnosed with Thalassemia-major, a blood disorder, and was dependent on blood transfusion every month, they said.

Thalassemia-major patients require frequent blood transfusions and their life expectancy is also less.

His parents were advised bone marrow transplant as the last resort to treat the child, but they could not find the required HLA (human leukocyte antigen) match.

"Due to unavailability of matching HLA donors for the transplant, we opted for IVF with HLA matching," city-based Nova IVF Fertility's medical director Dr Manish Banker told PTI.

This process of HLA typing is an established method for conceiving a child, who may donate cord blood or hematopoietic stem cells for transplantation to save a sibling with a critical illness.

Abhijeet's father approached Mr Banker after he found that the bone marrow of his family members, including the boy's elder sister, was not matching.

"Bone marrow transplant from an HLA-identical donor is the best therapeutic option for thalassemia major patients. We took the challenge and created a healthy savior sibling to save her elder brother," Mr Banker said.

With the help of IVF, Abhijeet's mother delivered a healthy baby girl Kavya a year ago, who was found to be the HLA match for the sibling.

In March this year, after Kavya gained the required weight, a successful bone marrow transplant was done for Abhijeet at the CIMS Hospital, Mr Banker said.

"Now, Abhijeet is risk-free and doesn't require blood transfusion," Mr Banker said.

"This is the first case in India when an HLA matching baby was born through IVF specifically to save the thalassemia-major sibling," he said.

The siblings' father, who himself researched well about this technique, thanked Mr Banker and other expert doctorsfor saving his son.

Excerpt from:
Child Conceived To Donate Bone Marrow Saves 6-Year-Old Brother's Life - NDTV

India just conducted its first successful experiment with savior sibling therapy, in which a baby was conceived through in-vitro fertilization for the purposes of donating bone marrow to an older ailing brother struggling with thalassemia, a condition characterized by low levels of hemoglobin in the blood that requires frequent blood transfusions. While the doctors involved in the therapy celebrated their success this week, some on social media challenged the ethics of such a therapy, in which a baby was essentially birthed to save her sibling.

In this case, the child with the genetic disorder needed a bone marrow transplant to cure his disease, and the chances of a successful cure are higher if coming from a person whose proteins (human leukocyte antigens, or HLA) exactly match those of the child. None of the childs existing family members was a match, further complicating the process of getting a bone marrow transplant an already difficult process to execute. The parents, in an effort to create a perfect bone marrow match for their child, underwent three cycles of in-vitro fertilization, out of which 18 embryos were created, and one perfectly matched that of the child, and was disease-free, using a technique called pre-implantation genetic diagnosis (PGD). The embryo was then implanted in the mothers uterus, carried to term, and a baby girl was born.

We had to wait for the baby to grow. She had to weigh 10 kg before we could draw bone marrow, Deepa Trivedi, program director of Sankalp Bone Marrow Unit in Ahmedabad, told The Hindu. Its been approximately seven months since the transplant, and the older sibling has not needed any more blood transfusions, indicating he has been cured of his thalassemia, his doctors announced.

Savior sibling therapy has already been used in countries such as the United Kingdom, the U.S.A., New Zealand, and France. Its mainly used to cure genetic blood disorders in children, such as sickle cell anemia or as seen in the Indian case, thalassemia major. The main way this is done, which is a departure from the Indian case, is by harvesting stem cells from a newborns umbilical cord, which are then injected into the bone marrow of the sibling with the disease, a practice that works 90% of the time. In case it doesnt, doctors can take bone marrow from the savior sibling as they grow, in a process that is painful but not known to be dangerous.

Related on The Swaddle:

Designer Babies Are Far From Reality, Even After the Gene-Edited Babies in China

The first ethical concern with this practice is treating a baby as a source for spare parts, as a means to an end, as a commodity. A study of the bioethics of savior sibling therapy, published in the Journal of Medical Ethics, surmised that treating a baby as a means to an end was not by itself a concern that devalued the utility of savior sibling therapy, as long as theyre also treated as human beings. Bioethicists surmise that using cord blood, something that is frequently discarded after birth, cannot endanger a newborn, or prove to be an ethical quandary used against the therapy.

But what has happened in the most recent case in India actually complicates the issue, because its not the umbilical cord blood that was harvested from the savior sibling at birth, but bone marrow 10 months into her life, which makes her an organ donor. This traverses thorny territory, as governments strictly regulate organ donation by minors due to issues related to consent. Can a baby consent to donating bone marrow to their sibling, or a 10-year-old consent to donating a kidney to their parent? It depends on where the individual resides, and how old the person being asked to donate is. In India, for example, it was only recently that the Delhi High Court ruled that minors could donate organs or tissues, as long as the procedure didnt pose a danger to their lives, and only in exceptional circumstances. However, where minors are mostly dependent upon their families, an element of coercion can also manifest. Also, determining whether a child rationally consented to donate an organ to their parent, for example, becomes difficult when we factor in the emotional element of their relationship that can perhaps override their judgments about their own safety.

Another concern is the well-being of the savior sibling throughout their life, both physical and psychological. Whats to stop a parent from asking the savior sibling to be on standby for their entire lives for their siblings health, available to be tapped for tissues and organs at any point in their lives? This is the plot of Jodi Picoults My Sisters Keeper (also turned into a film of the same name starring Cameron Diaz), but it is an unlikely scenario in real life, ethics experts have said. The aforementioned organ donation rules can prevent such an exploitative situation from arising, they say, with governments around the world tasked with ensuring the consent of the donor remains at the forefront of organ donation.

The third issue with savior sibling therapy arises out of the process itself if a parent can select an embryo that perfectly matches their child, whats to stop them from selecting an embryo for intelligence, or athleticism? This wades into the territory of the production of designer babies, which is an ethical slippery slope that critics have said goes against the natural reproductive order. However, the bioethics study asserts that the connection between savior sibling therapy and the production of designer babies is less of a slippery slope and more of a reach, as the technology might be similar, but the utility of both poles apart the former is used to save childrens lives, while the latter is a superficial, hypothetical fantasy.

For now, the world of savior sibling therapy, and its perception, remains similar to when parents first selected an embryo to create a savior sibling in the U.S. in 2000. As appeared in a New York Times article at the time, It is the kind of talk heard with every scientific breakthrough, from the first heart transplant to the first cloned sheep. We talk like this because we are both exhilarated and terrified by what we can do, and we wonder, with each step, whether we have gone too far. But though society may ask, How could you? the only question patients and families ask is, How could we not? 20 years later, savior sibling therapy still centers the children that can be saved, while government stipulations around the world try to ensure the savior siblings are protected, cared for, and treated as human beings, like any other child.

While a few critics argue for a ban, the bioethics study sums up the dilemma, and perhaps a solution to this ethical debate given that a ban will be fatal for a section of the population, the onus of proof rests clearly with the prohibitionists who must demonstrate that these childrens deaths are less terrible than the consequences of allowing this particular use of PGD.

You have got to have a very powerful reason to resist the means by which a childs life can be saved.

Read more from the original source:
An Indian Baby 'Savior Sibling' Just Gave Her Brother Bone Marrow. But Is It Ethical? - The Swaddle

Cecelia Ahern, the author of P.S. I love you, once beautifully said: Moments are precious; sometimes they linger and other times theyre fleeting, and yet so much could be done in them; you could change a mind, you could save a life and you could even fall in love.

Helping save lives is what we decided to dedicate some of our lives to at Manchester Marrow.More specifically, we are the student-ran arm of the charity Anthony Nolan, which signs up students/young people (aged 16-30 years) to the stem cell register. This is required in finding matches for patients suffering from blood cancers and blood disorders who desperately need transplants. The more people we sign up for this register, the higher the chance of finding a blood stem cell or bone marrow match.

Anthony Nolan was initially founded by Shirley Nolan in 1974, realising the hardships associated with requiring an urgent bone marrow transplant. This was due to her three-year-old son suffering from a rare blood disorder known as Wiskott-Aldrich Syndrome. This inspired her to set up the worlds first register to match donors with people in desperate need. Today, there are over 800,000 people on Anthony Nolans UK register list, and each of these people could be a potential donor and save a life.

Although there are many resources at hand, without you, theres no cure! In Marrow, we have three important missions: raise awareness of Anthony Nolan and blood cancer within UK universities through our events, encourage every student to join stem cell register through our donor recruitment opportunities, and lastly, raise funds to help support this vital work.

As a student, in addition to signing up to the register, you have the amazing opportunity of volunteering for us and to save a life! One of our most outstanding achievements is signing up over 100,000 people to the Anthony Nolan register and raising over 92,000 in a year. Additionally, 1 in 4 people who go on to donate stem cells is recruited via Marrow!

Being a volunteer for us is no hard work. You could do many things, including spreading the word and talking to people about why they should sign up to the register. Furthermore, you need to inform them what the donation involves if they ever found a match, checking medical backgrounds for donor eligibility, assisting them with cheek swabs, and filling out an application form.

If youre interested in this opportunity, there will be several volunteer training sessions held throughout the year. Unfortunately, due to the current situation, all these events will be held online. We can assure you, however, that were doing our best to make the most of it.

To sign up to the register visit the Anthony Nolan website!

Make sure to follow Manchester Marrows social media accounts to keep updated with all the news and events:

Facebook: @ManchesterMarrow

Facebook: Manchester Marrow Volunteers Group

Instagram: @manchestermarrow

Continued here:
Looking to save lives? Here's how - The Mancunion

DetailsCategory: DNA RNA and CellsPublished on Friday, 16 October 2020 14:20Hits: 378

First therapy recommended for full marketing authorization in the EU for eligible patients with confirmed diagnosis of late infantile or early juvenile MLD variants

One-time treatment with Libmeldy has been shown to preserve cognitive and motor function in most patients

Libmeldy is backed by data across 35 patients with follow-up of up to 8 years post-treatment, demonstrating the potential durability of HSC gene therapy

BOSTON, MA, USA and LONDON, UK I October 16, 2020 I Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending full, or standard, marketing authorization for Libmeldy (cryopreserved autologous CD34+ cells encoding the arylsulfatase-A, or ARSA, gene), an investigational gene therapy for the treatment of metachromatic leukodystrophy (MLD), characterized by biallelic mutations in the ARSA gene leading to a reduction of the ARSA enzymatic activity in children with i) late infantile or early juvenile forms, without clinical manifestations of the disease, or ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline.

The CHMPs positive opinion will now be reviewed by theEuropean Commission(EC), which has the authority to grant marketing authorization for Libmeldy in theEuropean Union(EU). A final decision by the EC for Libmeldy is anticipated before the end of 2020. If approved, Libmeldy would be the first commercial therapy and first gene therapy for eligible patients with early-onset MLD.

MLD is a very rare, severe genetic condition caused by mutations in the ARSA gene which lead to neurological damage and developmental regression. In its most severe and common forms, young children rapidly lose the ability to walk, talk and interact with the world around them. A majority of these patients pass away in childhood, with palliative care often as their only option.

Todays positive CHMP opinion for marketing authorization of Libmeldy is a remarkable achievement that we share with the MLD community, as it brings us closer to delivering a one-time, potentially transformative therapy for eligible children suffering from this devastating disease, said Bobby Gaspar, M.D., Ph.D., chief executive officer, Orchard Therapeutics. Data from the Libmeldy clinical program have demonstrated the potential for long-term positive effects on cognitive development and maintenance of motor function, translating to individual preservation of motor milestones such as the ability to sit, stand and/or walk without support, as well as attainment of cognitive skills like social interactions and school attendance, at ages at which untreated patients show severe motor and cognitive impairments.

Libmeldy is designed as a one-time gene therapy, developed in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy, in which the patients own hematopoietic stem cells (HSCs) are selected, and functional copies of the ARSA gene are inserted into the genome of the HSCs using a lentiviral vector before these genetically modified cells are infused back into the patient. The ability of the gene-corrected HSCs to migrate across the blood-brain barrier into the brain, engraft, and express the functional enzyme has the potential to persistently correct the underlying genetic condition with a single treatment.

This is an important milestone toward making the availability of HSC gene therapy a reality for more patients, and it also is extremely rewarding for our multi-disciplinary team at SR-Tiget who has worked relentlessly along this 15-year journey to move the seminal proof of principle studies to the first in-human testing of this therapy, said SR-Tiget director Luigi Naldini, M.D, Ph.D. The robust and durable clinical benefits observed in early-onset MLD patients who received HSC gene therapy are compelling, especially when compared to the natural history of the disease. These results also further illustrate our view that the HSC gene therapy approach has the potential to deliver transformative effects in other storage diseases as well, especially when the cells are designed to overexpress the functional enzyme and provide an enhanced supply of it to the affected tissues.

As a parent, watching your child start down a seemingly normal developmental path only to suddenly and rapidly lose some or all of his or her abilities is heart-wrenching, and the agony is even more acute knowing no approved therapies currently exist for MLD, said Georgina Morton, Chair of ArchAngel MLD Trust. Todays decision to advance Libmeldy to the final EC approval stage represents a huge step forward for the parents of these young children and for all of us in the MLD community.

We are extremely appreciative of the EMAs expedited and thorough review of Libmeldys marketing authorization application, considering the severity of MLD coupled with the limited treatment options available today for young patients, said Anne Dupraz, chief regulatory officer, Orchard Therapeutics. The Agencys collaboration on this assessment is a testament to their broader public health commitment to ensure timely evaluation of new medicines for diseases where a pressing unmet need exists.

Data Supporting the Clinical Profile of Libmeldy

The positive CHMP opinion is supported by clinical studies of Libmeldy in both pre- and early- symptomatic, early-onset MLD patients. Early-onset MLD encompasses the disease variants traditionally referred to as late infantile (LI) and early juvenile (EJ).

Clinical efficacy was based on the integrated analysis of results from 29 patients with early-onset MLD who were all treated with Libmeldy prepared as a fresh (non-cryopreserved) formulation:

Clinical safety was evaluated in 35 patients with early-onset MLD:

Co-primary endpointsThe co-primary endpoints of the integrated efficacy analysis were Gross Motor Function Measure (GMFM) total score and ARSA activity, both evaluated at 2 years post-treatment. Results of this analysis indicate that a single-dose intravenous administration of Libmeldy is effective in modifying the disease course of early-onset MLD in most patients.

Pre-symptomatic LI and EJ patients treated with Libmeldy experienced significantly less deterioration in motor function at 2 years and 3 years post-treatment, as measured by GMFM total score, compared to age and disease subtype-matched untreated patients (p0.008). The mean difference between treated pre-symptomatic LI patients and age-matched untreated LI patients was 71.0% at year 2 and 79.8% at year 3. Similarly, the mean difference between treated pre-symptomatic EJ patients and age-matched untreated EJ patients was 52.4% at year 2 and 74.9% at year 3. Although not statistically significant, a clear difference in GMFM total score was also noted between treated early-symptomatic EJ patients and age-matched untreated EJ patients (28.7% at year 2; p=0.350 and 43.9% at year 3; p=0.054).

A statistically significant increase in ARSA activity in peripheral blood mononuclear cells was observed at 2 years post-treatment compared to pre-treatment in both pre-symptomatic patients (20.0-fold increase; p<0.001) and early-symptomatic patients (4.2-fold increase; p=0.004).

At the time of the integrated data analysis, all treated LI patients were alive with a follow-up post-treatment up to 7.5 years and 10 out of 13 treated EJ patients were alive with a follow-up post-treatment of up to 6.5 years. No treatment-related mortality has been reported in patients treated with Libmeldy.

Key secondary endpointsFor EJ patients who were early-symptomatic when treated with Libmeldy, meaningful effects on motor development were demonstrated when these patients were treated before entering the rapidly progressive phase of the disease (IQ85 and Gross Motor Function Classification (GMFC)1). By 4 years post-disease onset, an estimated 62.5% of treated, early-symptomatic EJ MLD patients survived and maintained locomotion and ability to sit without support compared with 26.3% of untreated early-symptomatic EJ MLD patients, representing a delay in disease progression following treatment with Libmeldy.

A secondary efficacy endpoint that measured cognitive and language abilities as quantified by Intelligence Quotient/Development Quotient (IQ/DQ) found:

Clinical safetySafety data indicate that Libmeldy was generally well-tolerated. The most common adverse reaction attributed to treatment with Libmeldy was the occurrence of anti-ARSA antibodies (AAA) reported in 5 out of 35 patients. Antibody titers in all 5 patients were generally low and no negative effects were observed in post-treatment ARSA activity in the peripheral blood or bone marrow cellular subpopulations, nor in the ARSA activity within the cerebrospinal fluid. Treatment with Libmeldy is preceded by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative conditioning, which carry their own risks. During the clinical studies, the safety profiles of these interventions were consistent with their known safety and tolerability.

About MLD and Investigational Libmeldy

Metachromatic leukodystrophy (MLD) is a rare and life-threatening inherited disease of the bodys metabolic system occurring in approximately one in every 100,000 live births. MLD is caused by a mutation in thearylsulfatase-A(ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, gallbladder, kidneys, and/or spleen. Over time, the nervous system is damaged, leading to neurological problems such as motor, behavioral and cognitive regression, severe spasticity and seizures. Patients with MLD gradually lose the ability to move, talk, swallow, eat and see. Currently, there are no approved treatments for MLD. In its late infantile form, mortality at 5 years from onset is estimated at 50% and 44% at 10 years for juvenile patients.1Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase-A (ARSA) gene), formerly OTL-200, is being studied for the treatment of MLD in certain patients. Libmeldy was acquired from GSK inApril 2018and originated from a pioneering collaboration between GSK and the Hospital San Raffaele and Fondazione Telethon, acting through their jointSan Raffaele-Telethon Institute for Gene TherapyinMilan, initiated in 2010.

About Orchard

Orchard Therapeutics is a global gene therapy leader dedicated to transforming the lives of people affected by rare diseases through the development of innovative, potentially curative gene therapies. Our ex vivo autologous gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. In 2018, Orchard acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and theSan Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Orchard now has one of the deepest and most advanced gene therapy product candidate pipelines in the industry spanning multiple therapeutic areas where the disease burden on children, families and caregivers is immense and current treatment options are limited or do not exist.

Orchard has its global headquarters in London and U.S. headquarters in Boston. For more information, please visit http://www.orchard-tx.com, and follow us on Twitter and LinkedIn.

1 Mahmood et al. Metachromatic Leukodystrophy: A Case of Triplets with the Late Infantile Variant and a Systematic Review of the Literature.Journal of Child Neurology2010, DOI:http://doi.org/10.1177/0883073809341669

SOURCE: Orchard Therapeutics

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Orchard Therapeutics Receives Positive CHMP Opinion for Libmeldy for the Treatment of Early-Onset Metachromatic Leukodystrophy (MLD) | DNA RNA and...

INTRODUCTION

Over the past decade, there have been great successes in assembling high-performance biological and electronic materials with thin and sophisticated architecture. For example, monolayered cell sheets have shown to reproduce physiological activities of original tissue and exhibit enhanced therapeutic efficacy than individual cells because of increased cell-cell interactions and the presence of an extracellular matrix (14). These cell sheets are being studied extensively to assemble in vitro disease models and treat wounded or defective tissues and organs. Separately, minimizing the thickness of wearable electronic devices enables conformal adhesion without an interfacial gap and, in turn, improves performance for sensing, diagnosis, and therapies (58). However, handling such delicate and thin materials for transport and assembly remains a grand challenge. External forces used for gripping, holding, and discharging such materials often deform, wrinkle, or damage materials (9). Such damage can be avoided by attaching thin materials to sacrificial polymeric supports including water-soluble or thermal release tapes (1012). However, these supports should be removed with chemical or long-lasting heat treatment following the placement of thin materials onto a target site, thus making them not reusable.

Recently, efforts have emerged to transport thin electronic materials by simulating the ability of cephalopods (e.g., octopus and squid) to capture and release their preys (1315). Cephalopods use many muscle-based suction cups, called suckers, on their arms to attain conformal adhesion to target preys in both wet and dried environments (16, 17). Bioelectrical signals control the rapid contraction and relaxation of the soft muscle and, in turn, change the internal pressure of the suckers. However, most material-handling systems that were devised to mimic the suction cups focus on recapitulating the anatomical structure but overlook the roles of the bioelectrical signal for control. Therefore, these strategies require mechanical force to be applied externally to attach and detach materials of interests. In addition, synthetic suction cups made with polydimethylsiloxane (PDMS) or polyurethane acrylates are more rigid than biological suction cups by two or three orders of magnitude (13, 15). Such rigid suction cups require higher external pressure for gripping than biological ones, thus increasing the possibility to damage thin and soft materials. Certain efforts were made to assemble a device that can hold and detach materials with heat by coating porous PDMS with thermally responsive poly(N-isopropyl acrylamide) (PNIPAAm) (14). However, the manipulation process was only possible while submerged in a water bath. In addition, it takes 30 min to hours for the device to move one material from one place to another.

To this end, we demonstrate a soft manipulator that can repeat the holding and unloading of thin and fragile materials within 10 s in response to an electrical signal. We hypothesized that a rapid thermo-responsive, microchanneled hydrogel layered with a microelectric heater would lift and release materials of interests without applying an external force due to temperature-induced internal pressure change in microchannels of the gel (Fig. 1). In addition, gels tailored to be as soft as biological suction cups would allow fast and notable changes in internal pressure in response to small temperature changes while minimizing the amount of force imparted onto the thin material to be transported. We examined this hypothesis by attaching a flexible electric heater, which converts electrical signals into heat, to a microchanneled PNIPAAm hydrogel. We examined the extent that the electrothermal signal controls the shrinkage and expansion of microchannels of the gel along with subsequent pressure change inside microchannels. The resulting soft manipulator was assessed for its ability to lift up and release thin materials onto target tissues promptly in response to the electrothermal signal. These thin materials include therapeutic stem cell sheets and ultrathin, wearable bioelectronic devices.

Schematic illustration of (A) the soft, electrothermally controlled manipulator and (B) the process to transport a thin material using the soft manipulator. (A) The soft manipulator consists of a supporter, flexible heater that can convert electrical current to heat, cyanoacrylate-based wet adhesive, and a thermo-responsive PNIPAAm hydrogel with aligned microchannels. (B) Process to transport materials of interests using the soft manipulator. First, the soft manipulator is lowered to let the gel contact a thin material such as a therapeutic cell sheet or an ultrathin film device. During this step, the heater is turned on to contract microchannels of the gel. Second, the heater is turned off to open microchannels of the gel and generate negative pressure in microchannels. As a consequence, the gel serves to hold, lift up, and transport the thin material. Third, the heater is turned on to close microchannels of the gel and, in turn, generate positive pressure in the microchannels. The positive pressure serves to release the thin material onto the target surface.

We prepared a hydrogel that undergoes a rapid volumetric change in response to a temperature change by introducing anisotropically aligned microchannels into the PNIPAAm gel. The microchanneled gel was assembled by placing the pregelled NIPAAm solution on top of a liquid nitrogen reservoir. Then, ice crystals nucleated from the bottom and grew to the top surface due to the temperature gradient (step 1 in Fig. 2A). Simultaneously, solutes, including NIPAAm monomer, cross-linker, and photo-initiator in the solution, were separated from the growing ice crystals because of the decreased solubility in ice crystals (step 2 in Fig. 2A). This continuous and directional segregation of the solutes formed a cryo-concentrated phase between growing ice crystals. Subsequent exposure of the frozen sample to ultraviolet (UV) lightactivated polymerization and cross-linking reaction fixed the anisotropically aligned PNIPAAm network (step 3 in Fig. 2A) (18, 19). The final washing process with the water removed ice crystals and created a PNIPAAm gel with continuously aligned microchannels (Fig. 2B). The resulting gel exhibited an average microchannel diameter of ~20 4 m and an average wall thickness of 0.2 m in the gel at room temperature (Fig. 2C). The porosity reached 95 1%.

(A) Schematic illustrating the fabrication process of the gel with anisotropically aligned microchannels. The gel is prepared by directional crystallization and subsequent polymerization. (B) Photograph of the resulting microchanneled hydrogel after swelling in water. (C) Microstructure of the gel: (C-1) scanning electron microscopy (SEM) micrograph of the top surface, (C-2) 3D imaging of the microchanneled hydrogel via microcomputed tomography (micro-CT), and (C-3) SEM micrograph of microchannels that connect the top and bottom of the gel. (D) ESR of gels at different temperatures. (E) Compressive elastic moduli of gels. Samples were compressed in parallel with microchannel direction (axial compression) and perpendicular to microchannel direction (radial compression). (F) Time-dependent volumetric changes of microchanneled gel on heating (F-1) and cooling (F-2). The samples were placed on 40 or 25C plate. The resulting volumetric change was recorded. (G) Effective diffusion coefficient of water in gels quantified by the reswelling plot (F-2). * represents the statistical significance of the difference of values between conditions indicated with line (*P < 0.01). Photo credit: Byoungsoo Kim, University of Illinois at Urbana-Champaign.

For comparison, randomly oriented water crystals were created in the PNIPAAm gel by placing the pregelled NIPAAm solution in a freezer at 25C and curing it under UV light. The resulting hydrogel showed a similar porosity to the PNIPAAm gel prepared by directional crystallization. However, the microchannels of varying diameters were oriented randomly (fig. S1). In addition, PNIPAAm gel free of microchannels was prepared by skipping the crystallization step.

We examined the equilibrium swelling ratios (ESRs) of the resulting gels. All samples showed the volumetric swelling change at around 32C, which corresponds to the lower critical solution temperature (LCST) of PNIPAAm (Fig. 2D). The difference in the ESR between 25 and 35C was dependent on the microchannel architecture of the gel. In particular, gels with anisotropically aligned microchannels showed a 2.7-fold higher swelling ratio than those with randomly oriented microchannels and a 1.4-fold higher swelling ratio than those free of microchannels. The elastic modulus of the gel with anisotropically aligned microchannels was dependent on the direction of microchannels (Fig. 2E). The elastic modulus measured by compressing the gel perpendicular to the microchannel was 2.4 kPa, which was twofold lower than that measured by compressing the gel in parallel with the microchannels. In contrast, the gel with randomly oriented microchannels and the gel free of microchannels showed the minimal dependency of the elastic modulus on the direction of compression.

Next, we examined the extent that the microchannel architecture of the gel modulates the volumetric swelling rate in response to temperature change. The gel without microchannels exhibited minimal volumetric change over 10 s when the temperature was increased from 25 to 40C. In contrast, the gel with anisotropically aligned microchannels reduced its volume by 60% within 10 s when temperature increased to 40C (Fig. 2F-1 and movie S1). This heat-triggered shrinkage is attributed to the decrease of the average cross-sectional diameter of microchannels from 20 to 9 m as examined with scanning electron microscope images (fig. S2). The microchannel alignment was maintained during the shrinkage. The gel with randomly oriented microchannels also shrank within 10 s when temperature increased to 40C (Fig. 2F-1). However, the degree of shrinkage was approximately 0.4, which was 20% lower than the gel with anisotropically aligned microchannels. The electron microscopic images showed lots of open voids as well as micropores collapsed incompletely (fig. S3). In contrast, the gel with aligned microchannels exhibited a more uniform decrease in the microchannel diameter and minimal macro-sized voids after heating (fig. S2). This result indicates that micropores of varying diameters and orientation limit heat-induced collapse, thus leading to the decreased volume shrinkage.

Cooling the gel from 40 to 25C resulted in gel expansion. The speed and degree of volumetric expansion were dependent on the microchannel architecture. The gel without microchannels did not recover its original volume even after 1 hour (Fig. 2F-2 and fig. S4). In contrast, both of the gels with microchannels restored their original volume within 10 s due to reswelling. The reswelling plot displayed in Fig. 2F-2 was used to quantify the effective water diffusion coefficient (Fig. 2G). We used the Higuchi equation derived under the steady-state approximation of Ficks law of diffusion as follows (20)Vt=V25(S/V40)(Dt/)1/2(1)where Vt is the volume of a gel at time t, D is an effective diffusion coefficient, and S is an effective surface area. V40 and V25 are the volume of a gel at 40C and 25C, respectively. We assumed that water diffusion occurred exclusively on the gel surface. Anisotropically microchanneled gels had a 75-fold higher water diffusion rate than the gel free of microchannels (Fig. 2G). In addition, the gel with anisotropically aligned microchannels showed a 10% higher water diffusion rate than that of the gel with randomly oriented microchannels.

Separately, a flexible electric (joule) heater was fabricated to be attached to the gel by photolithographic patterning of a copper/polyimide film (thickness, 9-m copper/12-m polyimide). The linewidth and spacing of the copper pattern was kept at 300 m to provide uniform heat across the gel disk (Fig. 3A). The heater was additionally coated with a layer of tin (thickness, ~1 m) to prevent oxidation of the copper at an increased temperature within a humid environment. The heater was then connected to an external power supply with a voltage range of 2 to 5 V (Fig. 3B). The activated temperature was examined using an infrared camera, showing that the heater reached the target temperature at 37C within 5 s after applying a voltage of 2 V (Fig. 3, A and B). After the power was turned off, the temperature was dropped immediately back to 25C. Such electrothermal heater was attached to the gel disk using a cyanoacrylate-based adhesive (21). The bilayered hydrogel-heater construct was finally attached to a three-dimensional (3D) printed supporter (Fig. 3C).

(A) Photograph (top) and a thermal image of the flexible heater captured using an infrared camera (bottom). (B) Temperature change over time at differently applied voltages. The temperature profiles of the heater were obtained using an infrared camera. (C) Structural configuration of the soft manipulator (left) and a photograph of the soft manipulator (right). (D and E) Top: Snapshots of the microchanneled gel in the soft manipulator when the heater was turned on (D) and off (E). Images on the second row represent optical microscopic images of the gel surface when the heater was turned on and off. When the heater was turned on, aligned microchannels of the gel pushed water out while being closed for 20 s (D). When the heater was switched off, the gel in the soft manipulator opened microchannels and pulled water back into microchannels within 20 s (E). Scale bar, 100 m. Photo credit: Byoungsoo Kim, University of Illinois at Urbana-Champaign.

With the resulting electrothermal soft manipulator, we examined the response of the gel disk to the electrical signal. The test was conducted outside water. Figure 3 (D and E) shows the side view of the gel disk and the microstructural changes of the gel surface during the electrically controlled heating and cooling cycle. Switching on the heater triggered shrinkage of microchannels within 10 to 20 s and simultaneously released a fraction of water from the gel (Fig. 3D and movie S2). With the power off, the gel expanded the microchannels and reabsorbed the water within a few seconds (Fig. 3E and movie S2). The shrinkage and expansion of microchannels could be repeated hundreds of times by turning the power on and off. No structural failure of the gel was observed during repeated operation. We further examined the heat transfer through the gel layer placed on the heater at a temperature of 40C (fig. S5A and movie S3). With the heater on, the temperature of the gel increased rapidly from the bottom (point 1 in fig. S5B) to a top (point 4 in fig. S5B) within 20 s. This result confirms heat propagation along the gel thickness direction. The gel temperature increased at a rate of 0.3C/mms, independent of the region of observation. Last, the temperature of the entire gel became equal to that of the heater within 30 s (fig. S5C).

The gel with randomly oriented microchannels also underwent shrinkage and expansion in response to the electrothermal signal. However, the area undergoing microchannel shrinkage and expansion was not as uniform as in the gel with anisotropically aligned microchannels (fig. S6). Therefore, the gel released water locally. The gel without microchannels showed a very slow release and limited absorption of water when the electric heater was on and off, respectively (fig. S7).

The shrinkage and expansion of anisotropically aligned microchannels allowed the gel to grip, lift, and release materials of interest (Fig. 4A and movies S4 and S5). The manipulator with a diameter of 25 mm was used in this study. The manipulation process was conducted as follows. First, we shrank the upper part of the microchannels of the hydrogel by activating the heater (stage 1 in Fig. 4A). During this process, the gel released a fraction of water, thus creating an empty pocket between the heater and residual water in the microchannels. The gel was then placed on a 4-inch-diameter silicon wafer, a model material that should be transported (stage 2 in Fig. 4A). Next, the heater was deactivated to expand the shrunken microchannels and move residual water upward [stage 3 (i) in Fig. 4A]. The subsequently formed vacant space between water within the microchannels and the silicon wafer decreased the pressure inside microchannels, thus making the gel adhere to the silicon substrate. Thus, the soft manipulator could lift the substrate [stage 3 (ii) in Fig. 4A]. Last, with the power on, microchannels adjacent to the heater shrank and pushed water out of the microchannel (stage 4 of Fig. 4A). The subsequent pressure increases inside the microchannels served to dislodge the silicon wafer quickly. This mechanism is distinct from artificial handling systems assembled with an inspiration from anatomy of the cephalopods suction cup. These handling systems, however, require external force to hold and release materials of interest. In contrast, the manipulation process performed by our soft manipulator resembles the neuromuscular actuation in which cephalopods grip and release materials of interests. Through control of electricity, the rapid electrothermal actuation of the gel enabled the manipulator to systematically lift up and release target materials without external forces.

(A) Snapshots showing the transport of a 4-inch-diameter silicon wafer using a soft manipulator (upper images). Schematic illustrating the shrinkage and expansion of microchannels and subsequent water movement in microchannels controlled by the electrothermal signal (bottom images). The operating power of the soft manipulator was 5 W. (B) The time-dependent variation of normal adhesion strength measured by the dynamic mechanical analyzer (DMA) during stages 2 and 3 in (A). An initial contact strength of 0.05 kPa was applied to the soft manipulator for this measurement. (C) Fluorescence images of water in microchannels of the gel. The image was obtained from a 3D z-stack confocal microscope before (top) and after adhesion (bottom) of the soft manipulator to a target surface. The heater was attached to the upper part of the gel. (D) Dependency of the adhesion strengths on the initial load. (E) Variation in the adhesion strength as a function of cycle number. (F) Adhesion strength of the soft manipulator measured with the various target substrates in water and air. An initial contact strength of 0.5 kPa was applied to the soft manipulator using DMA for this measurement. Photo credit: Byoungsoo Kim, University of Illinois at Urbana-Champaign.

The normal pressure development of the gel to the silicon surface was further measured, particularly during stages 2 and 3. This measurement was conducted by attaching the bilayered gel-heater construct to a dynamic mechanical analyzer (DMA) (Fig. 4B). First, the gel was preheated by the heater and brought into contact with a 4-inch silicon wafer (Approaching stage in Fig. 4B). Next, when the power was turned off to expand microchannels, the load was increased in the negative direction for 25 s (Gel expansion stage in Fig. 4B). This bilayered gel-heater construct was then slowly pulled upward at 0.1 mm/s by DMA to monitor the increase of the adhesion strength (Adhesion stage in Fig. 4B). The maximum adhesion strength reached 1.5 kPa. Once the power was turned on before the stress reached 1.5 kPa, the normal adhesion strength decreased quickly to 0 kPa within 5 s (Unloading stage in Fig. 4B).

Without temperature control, the manipulator does not exhibit adhesion. We further examined whether temperature-induced contraction and expansion of microchannels are essential to create adhesion. The soft manipulator preheated to 37C was placed on the silicon wafer immersed in water with controlled temperatures. Then, the heater of the soft manipulator was turned off. At temperatures below LCST of the gel layer (i.e., ~32C), the adhesion strength increased rapidly with decreasing temperatures (fig. S8). This result confirms that temperature of the heating layer in the manipulator controls the degree of expansion of the microchanneled gel layer and, in turn, regulates adhesion strength.

We propose that the electrothermally controlled adhesion of the gel to the silicon wafer results from the pressure difference (P) between two ends of microchannels. We introduced the mixture of rhodamine B and water into microchannels of the gel and monitored the vertical movement of water through the individual microchannel during stage 3 (i) in Fig. 4A. According to the side view of the gel captured with confocal microscopy, the microchanneled gel disk was fully filled with water (Fig. 4C, top). Heating and the subsequent cooling process resulted in the space in the lower part of the microchannel adjacent to the silicon substrate by moving residual water upward in the microchannels (Fig. 4C, bottom). This image is similar to the scheme that represents stage 3 in Fig. 4A. The average height of space in the microchannel was approximately 50 m. The pressure difference of a single microchannel in the gel was quantified with a height of the empty part in the microchannel as followsP=wg(hihf)(2)where w is the density of water, g is the gravitational acceleration, and hi and hf are the height of the space in microchannels when the power was turned on and off, respectively. According to the calculation, each microchannel in the gel produced 0.5 Pa of negative pressure after the cooling process.

The adhesion strength of the gel to the silicon wafer was dependent on the initial load applied to the soft manipulator (Fig. 4D). The maximum adhesion strength reached 65 kPa with the initial pressure of 5.0 kPa. The maximum adhesion strength reached 65 kPa with the initial pressure of 5.0 kPa. To underlie the mechanism, we examined the normal pressure development that varies with the initial contact pressure using a DMA. As shown in fig. S9A, the heated soft manipulator was placed on the target silicon wafer. As soon as the heater was turned off, the gel layer expanded and pushed the silicon wafer more strongly. As a consequence, the normal pressure developed in the opposite direction. The normal pressure increased with the initial contact pressure (fig. S9B). Increasing the initial contact pressure enlarged the effective suction area of the soft manipulator and also augmented the normal pressure.

We also examined the effect of elastic modulus of target materials on the adhesion strength. We prepared alginate hydrogels with elastic moduli of 22.5 and 69.8 kPa as target materials for transport (fig. S10A). As confirmed with the pressure development profiles, with a given initial contact pressure of 0.25 kPa, the soft manipulator exhibited a similar magnitude of the adhesion strength to the alginate gels as well as the silicon wafer with a much higher elastic modulus of 140 to 180 GPa. This result suggests that it is not necessary to vary the initial contact pressure with the target material stiffness (fig. S10B). The adhesion strength was not reduced during the repeated cycles of closure and opening of microchannels (Fig. 4E). No chemical contamination or residue was observed on the silicon wafer after the process (fig. S11). The soft manipulator could transport plastic and glass materials by exerting a similar magnitude of the adhesion strength regardless of material hydrophobicity (Fig. 4F). The soft manipulator functioned to transport materials immersed in aqueous media and those in the air.

Last, we examined the capability of the soft manipulator to lift up, transport, and release ultrathin and delicate materials, such as living cell sheets and ultrathin thin film devices. We prepared a single-layered mouse skeletal myoblast cell sheet on a culture dish. In general, monolayered cell sheets were easily damaged or crumpled when picking up the sheet from the cell culture dish with forceps (Fig. 5A and movie S6). By switching the heater of the soft manipulator on and off, it was possible to lift the myoblast cell sheet and transport them to the new target sites. First, we transferred the cell sheet to a glass dish using the soft manipulator (Fig. 5B). Then, we examined whether the soft manipulator damages the sheet during transplantation. Off-axis deformation and viability of the cell sheet before and after delivering process were measured using the spatial light interference microscopy (SLIM) and the live-dead assay kit, respectively. According to SLIM observation and live-dead assay results, there was no substantial wrinkling nor loss of viability of cells that formed the cell sheet during this transport process (Fig. 5C and fig. S12). This simple transportation process allowed us to fabricate a 3D tissue by stacking multiple myoblast sheets using the soft manipulator (Fig. 5D). The resulting three-layered myoblast tissue showed a dense construct with three different layers.

(A) Snapshots of a process to pick up a skeletal myoblast sheet with forceps. The cell sheet was deformed when picking up the sheet using forceps (right). The cell sheet was stained with methylene blue for visualization. (B) Snapshot of a process to transport the skeletal myoblast sheet onto a glass surface using the soft manipulator. (C) Spatial light interference microscopy (SLIM) images of the cell sheet before (left) and after (right) the transfer, showing off-axis diffraction of the cell sheet. (D) Fluorescence image of a multilayered cell sheet consisting of three different myoblast sheets. The multilayered sheet was prepared by stacking cell sheets using the soft manipulator. (E) Snapshots of a process to transport a skeletal myoblast sheet onto a muscle tissue. It took 30 s for the entire transfer process. (F) Photographs of a rat eye before and after transplantation of a stem cell sheet. The cell sheet transplanted to the corneal epithelium of a rat eye using the soft manipulator. It took 30 s for the entire transfer process. (G) Histological examination of the rat eye before (left) and after (right) a stem cell sheet transfer. Hematoxylin and eosin staining revealed that the stem cell sheet was able to be successfully transplanted onto the anterior corneal surface without substantial interface space generation. Photo credit: Byoungsoo Kim, University of Illinois at Urbana-Champaign.

The soft manipulator allowed us to pick up various types of cell sheets and deliver them rapidly to any target surfaces. As a demonstration, we delivered the myoblast cell sheet to an ex vivo muscle tissue without any structural breakages (Fig. 5E and movie S7). The entire transport process could be completed within 30 s. In contrast, the soft manipulator assembled using a gel with randomly oriented micropores could not uniformly deliver the cell sheet due to the nonuniform micropore shrinkage (fig. S13). We also used the soft manipulator as a device to support atraumatic transplantation of a stem cell sheet to the anterior surface of the cornea. Similar to the myoblast cell sheet, mesenchymal stem cell sheets on a donor substrate could be easily transferred to the corneal epithelium of a rat eye (Fig. 5F). We confirmed the stable attachment of the stem cell sheet to the anterior surface of the cornea, in the position of the corneal epithelium of the rat eye by histological observation (Fig. 5G). A method to atraumatically transplant ex vivo generated stem cell sheets could simplify surgical technique and expand access to corneal epithelial stem cell transplants and it could have useful application in the treatment of corneal epithelial injuries, persistent epithelial defects, limbal stem cell deficiencies, nonhealing corneal ulcers, and blast injuries (22, 23).

In addition, the soft manipulator was used to transport an ultrathin electrophysiological (EP) sensor (thickness, ~1 m) without causing wrinkling. We fabricated the EP sensor that consists of reference, ground, and measurement electrodes allowing high-quality recording of electrocardiogram (ECG) signals (Fig. 6A) (24, 25). Generally, such ultrathin film devices were easily crumpled when picking up from a donor substrate, which typically requires the use of a temporary handling support (fig. S14 and movie S8). By using the soft manipulator, it was possible to controllably transfer the EP sensor from the donor substrate to the surface of the pig heart within a minute (Fig. 6B and movie S9). No substantial wrinkles were observed after completing the transport (Fig. 6C). A waveform generator was used to apply a preprogrammed ECG signals across the pig heart using an Ag/AgCl electrode. The resulting ECG signals captured from the EP sensor were nearly identical to those generated from the waveform generator (Fig. 6D and fig. S15). The Pearsons correlation coefficient of the signals was 0.98.

(A) Device configuration of the ultrathin EP sensor (t = 1 m) tailored for the measurement of ECG signals. (B) Snapshot of a process to transport the device to the surface of the pig heart. It took 30 s to capture and deliver the device onto the pig heart. (C) Photograph of the device transplanted to the pig heart using the soft manipulator. (D) Representative ECG signals measured using the transplanted device. Photo credit: Byoungsoo Kim, University of Illinois at Urbana-Champaign.

Together, this study demonstrates that the soft manipulator assembled by integrating a rapid thermal-responsive microchanneled gel and an electrothermal heater can transport ultrathin biological and electronic materials quickly and safely. The resulting soft manipulator could be switched on and off with electricity to lift and release thin and delicate materials within tens of seconds. This rapid handling could be attained with the electrothermally controlled change in the adhesion force between the soft manipulator and target materials. Such an actuation mechanism is very similar to the muscular action of cephalopod suction cups. Therefore, this soft manipulator is distinct from previous suction cupmimicking platforms that need external force for detachment of materials. In addition, the soft manipulator could move thin materials of interest in both wet and dry conditions. Using this unique functionality, we could assemble multilayered cell sheets and place an ultrathin biosensor to the target tissue without impairing its function.

We envisage that further modification of this soft manipulator with an electronic sensor would allow robots to transport ultrathin materials autonomously. For instance, the resulting smart soft manipulator would be able to monitor the degree of deformation of transporting materials during contact and, in turn, adjust the suction force to a level at which materials retain their structural integrity and functionality. By doing so, the soft manipulator would improve its performance from the standpoint of safety and accuracy of material handling and assembly. We believe that the present design concept may be widely used as a new soft handling tool for the fabrication of ultrathin film devices, tissue engineering, and transplant surgery.

This study demonstrated an electrically controllable soft machinery useful to transport ultrathin, delicate objects, including therapeutic cell sheets and thin, wearable biosensing devices. This system, named as the electrothermal soft manipulator, consisted of a flexible heater attached with a rapid thermo-responsive PNIPAAm hydrogel disk with controlled microchannel architecture and tissue-like softness. Compared with hydrogels free of microchannels or those with randomly oriented microchannels, the anisotropically aligned PNIPAAm hydrogel could shrink and expand in response to the electrically induced heat much faster, on the order of seconds. Such a fast-volumetric change of the microchannels on the surface of an object could produce and remove pressure-induced adhesion repeatedly. This controlled actuation mechanism is similar to the activity of cephalopod suction cups that hold and release objects of interest using bioelectric signals. As a consequence, the soft manipulator could move thin biological and bioelectronic devices quickly in both wet and dry conditions without causing wrinkling or damage of the thin materials. Such an electrothermally controlled soft manipulator would be useful to various applications that require the sophisticated manipulation of fragile and delicate biological tissues and bioelectronic devices.

NIPAAm (1.25 g) and N,N-methylenebisacrylamide {12.5 mg [0.01 weight % (wt %) of NIPAAm]} were dissolved in distilled water (8.75 ml) for 1 day at 25C to ensure the complete dissolution. Then, 25 mg (0.5 wt % of NIPAAm) of radical photo-initiator (Irgacure 2959) was added into the obtained solution and stirred until all the solids completely dissolved. The resulting pregelled NIPAAm solution was poured onto a Si-wafer substrate (4 inches, 550 m thick) with silicone mold (50 mm by 50 mm by 1 mm or 20 mm by 20 mm by 10 mm). Then, the Si-wafer substrate was put on a liquid nitrogen reservoir for the directional crystallization of the pregelled NIPAAm solution. The distance between the bottom surface of the Si-wafer and the top surface of liquid nitrogen was 1 cm. After complete crystallization of the pregelled NIPAAm solution, the samples were irradiated with a UV lamp ( = 365 nm) for 6 hours at a 25C freezer for the radical cryo-polymerization. The as-prepared poly-NIPAAm gel (PNIPAAm) was then washed with fresh water three times to remove the ice crystals.

For comparison, PNIPAAm gel with randomly oriented microchannels was prepared by placing the pregelled NIPAAm solution in a freezer at 25C for random crystallization. Then, the resultant samples were cryo-polymerized and washed at the same condition described above. PNIPAAm gel free of microchannels was prepared by skipping the crystallization and subsequently irradiated with a UV lamp for 1 hour at 4C. All hydrogel samples were soaked in 250-ml distilled water at 25C, which was repeatedly replaced for 1 day to remove unreacted impurities before using them.

The morphology of microchanneled PNIPAAm gels was examined using an environmental scanning electron microscope (ESEM; Quanta FEG 450, FEI) and microcomputed tomography (micro-CT, MicroXCT-200, Xradia Inc.). For cross-sectional analysis, the samples were immersed in liquid nitrogen for 30 min and immediately cryo-fractured. One hundred points from 10 different ESEM images were taken to determine the average pore size. The porosity of gels was determined by the gravimetric method. The pore volume of gels was divided by the total volume of gels as followsPorosity(%)={(WswollenWdry)/w}/{(WswollenWdry)/w+(Wdry/PNIPAAm)}(3)where Wswollen and Wdry are the weights of swollen and dry gels, respectively; w is the water density; and PNIPAAm is the NIPAAm density (1.1 g/cm3).

For ESR measurement, we measured the weight of PNIPAAm gels at different temperatures (4 to 40C) with 4C increments. The ESR was defined using the following equationESR(%)={(WsWd)/Wd}100(4)

The hydrogel samples were equilibrated at each temperature for 12 hours and weighted (Ws) after removing excess water. The dry weight of the samples (Wd) was measured after lyophilization. Five samples of each PNIPAAm gel were averaged.

For dynamic deformation analysis of hydrogels in response to temperature change, hydrogel samples immersed in 25C were trimmed into a cylinder shape (d = 25 mm, t = 1 mm) and placed on a copper plate (t = 1 mm). Then, the plate was put onto a heated Peltier stage (40C) to investigate the deswelling kinetics of samples. For reswelling kinetics, deswelled samples were transferred to a cooled Peltier stage (25C). We monitored the volume change in response to temperature using an optical microscope that connected with the Peltier device (TP104SC-mK2000A, Instec). All optical images were analyzed using ImageJ software.

The compressive modulus of hydrogels was measured on an electronic universal testing machine (Instron 5943, Instron) equipped with a water bath. Samples were cut into a square shape (10 mm by 10 mm by 10 mm). All mechanical tests were conducted in a water bath (25C). There were five replicates for all mechanical tests.

The heater was fabricated on a copper/polyimide film (t = 9 m/12 m, Pyralux AC091200EV, Dupont). A standard photolithographic patterning with a dry film photoresist (Riston MM540, Dupont) followed by the wet etching method (CE-100, Transene Inc.) defined the copper layer into a joule heating element. The copper traces were coated with 1-m layer of tin (Sn) (421 Liquid Tin, MG Chemicals) to protect the copper from oxidation in elevated temperatures within a humid environment. The resulting heater was then connected to an external power supply, where a voltage range of 2 to 5 V and its thermal characterizations over time were recorded using an infrared camera (E40, FLIR Systems).

The cyanoacrylate-based adhesive was spread on top of the flexible heating array (21). Immediately after, the hydrogel was trimmed into a cylinder shape (d = 25 mm, t = 1 mm) and pressed onto the substrate. The bonding occurs within 30 s. The resulting gel/heater was attached to a 3D printed supporter using double-sided tape (VHB, 3M). Then, the soft manipulator was connected to an electrical power supply.

For dynamic deformation analysis of the soft manipulator in response to activation of a heater, a monochrome camera (DS-Qi2, Nikon) was attached to an optical microscope (Eclipse LV100, Nikon) for top-view analysis of the gel in the soft manipulator. A digital camera with an optical zoom macro lens (Canon, MP-E 65 mm) was used for the side view analysis of the soft manipulator. Gels in the soft manipulator were incubated with colored water (Green, McCormick) for visualization of water.

Adhesion tests were performed with a DMA (ESM303, Mark-10). The soft manipulator was mounted on a load cell of the DMA (M5-5 or M5-200, Mark-10), and the vertical approach and retraction speeds of the soft manipulator were 0.1 mm/s. Force-displacement profiles with time were measured at room temperature.

To examine the capability of the soft manipulator to handling materials with different elastic moduli, alginate hydrogels with elastic moduli of 23 and 70 kPa were used in this study. Pregelled alginate solution was prepared by mixing 2 wt % alginate solution in MES buffer (pH 6.5) with sulfonated N-hydroxysuccinimide and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. Then, the pregelled alginate solution was cross-linked by adding adipic acid dihydrazide (AAD). The elastic modulus of the alginate gels was controlled by varying the molar ratio between AAD and uronic acids of alginate (MAAD).

Cross-sectional fluorescence images were obtained from 3D z-stack confocal images (LSM 880, Carl Zeiss). We used Rhodamine B mixed with water for tracking of water inside the soft manipulator before and after the attachment process.

To investigate surface contamination of the soft manipulator, we performed adhesion tests to silicon wafers using either the soft manipulator or a commercial medical grade tape (Transpore, 3M). After detachment of the samples, the resulting wafer was incubated with a dye (Rhodamine B) for 30 min. All samples were washed with distilled water three times in total. Then, we dried the wafer surface using N2 gas and subsequently observed the wafer surfaces using fluorescent optical microscopy.

C2C12 cells (mouse skeletal myoblast cell line, CRL1772) and D1 cells (bone marrowderived mesenchymal stem cell line, CRL12424) were obtained from the American Type Culture Collection (ATCC). C2C12 or D1 cells were plated on temperature-responsive PNIPAAm-grafted culture dishes (d = 35 mm, UpCell, Thermo Fisher Scientific) with seeding density of 5 105 cells. The cells were then cultivated for 3 days according to the guidelines of ATCC. To harvest sheets, confluent cells were rinsed twice with warmed Dulbeccos phosphate-buffered saline (DPBS). Then, the monolayers were detached from the culture dish by lowering the incubation temperature from 37 to 20C.

The viability of cell sheets was examined using the LIVE/DEAD Viability/Cytotoxicity Assay Kit for mammalian cells (Invitrogen) according to the manufacturers instructions. The cultured cells or transferred cells were gently washed three times with DPBS. Calcein acetoxymethyl (AM) and ethidium homodimer-1 (EthD-1) were diluted together in DPBS. Diluted calcein AM and EthD-1 solution (1 ml) was added to cultured cells and kept for 45 min at room temperature. The live cells were stained with calcein AM, and dead cells were stained with EthD-1. After staining, cells were gently washed with 1 DPBS for three times and imaged with a fluorescence microscope (LSM-880, Carl Zeiss). Off-axis deformation of the cell sheets before and after the delivery process was quantified using SLIM. The optical system was assembled by attaching a SLIM module (CellVista SLIM Pro, Phi Optics) to the output port of an existing inverted phase-contrast microscope (26).

C2C12 cells were cultured onto a temperature-responsive culture dish to produce cell sheets as described above. After incubation, confluent cells were stained with Cell Tracker Orange CMRA (Invitrogen) or calcein AM (Invitrogen). Then, cell sheets were detached from the culture dish by lowering the incubation temperature from 37 to 20C. The detached cell sheets were captured and transferred using the soft manipulator with electrical heater control. A multilayered cell sheet was fabricated by repeating the transfer procedure. The resulting multilayered tissue structure was imaged using a fluorescence microscope (LSM-880, Carl Zeiss).

Long-Evans/BluGill rats were used in this study. All experimental protocols were in compliance with the National Institutes of Health Public Health Service Policy on Humane Care and Use of Laboratory Animals and were approved by the University of Illinois at Urbana-Champaign (UIUC) Institutional Animal Care and Use Committee. For fixation of the cornea, the perfusion needle was inserted into the left ventricle of the heart. A cut was made within the right atrium to allow blood evacuation. Saline was injected at a rate of 300 ml/min to clear the blood from the rat, followed by injection of paraformaldehyde (PFA) at 300 ml/min. The perfusion was confirmed by checking PFA dripping from the nose of the rate, stiffening of the extremities and the liver, and contractures of the musculature. After completing the perfusion, the stem cell sheet was placed on the rats cornea using the soft manipulator. The other rat eye was used as a control. Enucleation was then performed using microscissors.

Enucleation was followed by placement of the eyeball on dry ice then into a mold. The mold was subsequently filled with an optimal cutting temperature (OCT) compoundembedding medium to ensure OCT. Cryosectioning at 40-m slices was performed using a cryostat. Slices were then fixed using 4% PFA because the eyeball was fixed but not the stem cell sheet. The sample was washed three times in tris-buffered saline (TBS) for 5 min. The section was stained with hematoxylin and eosin staining, followed by dehydration in citrasol for 5 min. The stained tissue section was imaged using Axio Zoom.V16.

The fabrication of the EP sensor began by spin-coating a layer of poly(methyl methacrylate) (PMMA; ~1 m thick) on a glass substrate, followed by thermal annealing at 180C for 1 min. A subsequent layer of polyimide (~1 m thick) was coated and cured in a vacuum oven at 250C for 1 hour. Thin films of Cr and Au (t = 5 nm/150 nm thick) were deposited by using an electron beam evaporation. Photolithographic patterning using a negative-type photoresist (Riston MM540, DuPont) followed by wet etching with Au and Cr etchants (Transene) defined the joule-heating element. The resulting structure was submerged in acetone to dissolve the bottom PMMA layer. An anisotropic conductive film (ACF; HST-9805-210, Elform) was bonded to the terminals and was connected to an external data acquisition system. The measurement of ECG signals began by attaching two commercial conducting electrodes (30 mm by 24 mm, H124SG, Kendall) diagonally across the pig heart. The electrodes were then connected to an arbitrary waveform generator (3390, Keithley) to apply a preprogrammed cardiac waveform (1-Hz frequency, 50-mV amplitude). The EP sensor was transferred onto the surface of the pig heart with the soft manipulator. The sensor was connected to an external preamplifier (Octal Bio Amp, ADInstruments) and data acquisition unit (PowerLab 16/35, ADInstruments), where the captured ECG signal was digitally filtered with a band-pass filter at the bandwidth of 0.5 to 100 Hz.

Acknowledgments: Funding: This work was supported by the National Science Foundation (STC-EBICS grant nos. CBET-0939511 and CBET-1932192), the National Institutes of Health (1R21 HL109192), the Department of Defense Vision Research Program under Award (W81XWH-17-1-022), and the Jump ARCHES endowment through the Health Care Engineering Systems Center at University of Illinois at Urbana-Champaign and partly by Korea Institute of Science and Technology-Europe. C.H.L. is funded by the NIH National Institute of Biomedical Imaging and Bioengineering (NIBIB: 1R21EB026099-01A1). E.E.H. acknowledges the financial support from the University of Illinois Beckman Institute Graduate Fellowship. H.C. and N.M. gratefully acknowledge funding support from the National Science Foundation under award no. 1554249 and the International Institute for Carbon Neutral Energy Research (WPI-I2CNER), sponsored by the Japanese Ministry of Education, Culture, Sports, Science and Technology. V.K.A. acknowledges financial support from National Institutes of Health, National Eye Institute K08 EY024339 and R01EY029409; Department of Defense, Congressionally Directed Medical Research Program, Vision Research Program W81XWH-17-1-0122 (V.K.A. and H.K.); Veterans Affairs Office of Research and Development I01BX004080; Unrestricted Grant from Research to Prevent Blindness, New York; and National Institutes of Health, National Eye Institute P30 EY001792. Author contributions: B.S.K. and H.K. designed this project and wrote the manuscript. M.K.K., Y.P., and C.H.L. developed the flexible heater and performed the electrophysiology recordings. Y.C. and S.G.I. supported the cell sheet preparation. E.E.H. and M.U.G. performed and analyzed animal experiments. H.C. and N.M. helped to investigate electrothermal actuation of the gel. K.M.S. and L.B.S. supported and advised on animal experiments. V.K.A., K.K., and K.-N.S. advised on the tissue transplantation. C.H. and G.P. performed SLIM observation of the cell sheet, W.C.B. and S.Y. performed adhesion tests, B.S.K. performed all other experiments. J.L., C.H.L., and H.K. supervised the project. All authors discussed the results and contributed to the final version of the manuscript. Competing interests: H.K., B.S.K., C.H.L., J.L., and M.K.K. are inventors on a provisional patent application related to this work filed by the University of Illinois at Urbana-Champaign, Purdue University, and Chung Ang University (filed on 31 August 2020; no. 63/072,634). The authors declare no other 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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Electrothermal soft manipulator enabling safe transport and handling of thin cell/tissue sheets and bioelectronic devices - Science Advances

by Manasi Vaidya in New York.

Fate TherapeuticsandCelyadsnatural killer (NK) cell biology-focused cell therapies could overcome cell persistence challenges and consequent efficacy concerns with redosing strategies, experts said.

One of Fate Therapeutics lead products, FT596, is an allogeneic, multitargeted, chimeric antigen receptor (CAR) NK cell product. Celyads autologous CYAD-01 and CYAD-02 and allogeneic CYAD-101 are CAR T cell products using NK cell specificity to target T-cells. One analyst considered the potential to redose allogeneic products as a key item to consider while assessing clinical potential. While clinical data establishing the additive efficacy advantages of giving multiple doses is still preliminary, redosing allogeneic products could increase their expansion and persistence, experts said. Autologous therapies carry source constraints, so the ability to manufacture and administer allogeneic therapies is an advantage, they said.

While past NK cell therapy data has been mixed, experts saw potential in CAR NKs like FT596 or CAR T-cell products engineered to express NKG2D like CYAD-101, given the advancements in cell production.

Phase I FT596 results in B-cell lymphomas/ CLL are expected at either the American Society of Hematology (ASH) meeting in December or an investor meeting in early 2021, as per a second analyst report. Phase I data for CYAD-01 and CYAD-02 in relapsed/refractory (r/r) acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are expected by YE20, as per the companys August corporate presentation. Celyads allogeneic CYAD-101 is being tested in a Phase I alloSHRINK trial (NCT03692429) in metastatic colorectal cancer (CRC), which has a primary completion date of November 2020.

FT596s sales are expected to reach $136m in 2026, according to a GlobalData Consensus forecast. Celyad did not respond to a request for comment.

Increasing the persistence of cell therapies once they are infused into a patient has been a challenge, especially with NK cell-based therapies, experts said. The issue of persistence and consequent efficacy is significant because the potential efficacy with Celyad and Fate Therapeutics platforms remains largely unknown, they added.

Because the immune system can recognise foreign cells, cell products would not last for more than a few weeks, said Dr Marco Davila, medical oncologist, in the Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, Florida. With CAR T-cell therapies, the expansion and persistence of CAR cells are said to correlate with the durability of response, said Dr David Sallman, assistant member, Department of Malignant Hematology, Moffitt Cancer Center.

Strategies involving multiple doses of cell therapies could maximise the total dose, improve duration, and increase efficacy magnitude with both autologous and allogeneic cell therapies, said Dr Tara Lin, associate professor of medicine, University of Kansas Medical Center, Kansas City. Multiple infusions of therapy could also potentially lead to complete remission, said Sallman. In Fate Therapeutics Phase I FT500 (NCT03841110) study, patients had been given up to six doses of the therapy, which was not found to be toxic, according to Fate Therapeutics CEO Scott Wolchko. Redosing has the potential to offer multiple infusions as maintenance therapy, said Dr Jeffrey Miller, professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis.

The persistence of allogeneic therapies is not well understood, and it is unknown how long cells need to persist to be effective or whether persisting cells confer durability of response, said Wolchko. Giving multiple doses is one way to overcome the lack of persistence if it is an important factor for efficacy, he said. In a 4Q19 call, the FDA said it was allowing the dose to be repeated on a patient-by-patient basis, Wolchko said. In the alloSHRINK study, CYAD-101 is administered three times with a two-week interval between each administration in metastatic CRC, as per ClinicalTrials.gov.

However, even if the engineered cells do not persist in the body, the response rate and ability to eradicate the disease should not be limited, said Davila. With a limited lifespan, allogeneic cell therapies would dissipate as the patients immune system recovers, said Dan Kaufman. With the incorporation of interleukin (IL)-12 or IL-15 into the cell product, the cell therapy could persist without exogenous cytokines, said Kaufman. The FT596 construct contains an IL-15 fusion protein.

Experts cited the data from a Phase I / II (NCT03056339) investigator-led effort at MD Anderson Cancer Center using cord blood-derived anti-CD19 CAR NK cells as an example of an effective CAR NK therapy. The study by Rezvani and colleagues showed a persistence challenge did not seem to hamper the response, because once a critical threshold for cell expansion is crossed, the activity can be mediated, Davila said. Eleven r/r patients with CD19-positive cancers, such as non-Hodgkins lymphoma or CLL, were treated with a single infusion; eight had a response, including seven with a complete remission (Rezvani et al. [2020] N Engl J Med, 382, pp. 545553). Even if the cells do not persist, they expand to sufficient levels to eradicate the disease before they are lost, Davila added.

In the Phase I THINK(NCT03018405) CYAD-01 data, decreased bone marrow blasts were observed in eight patients, including five objective responses and one stable disease for three or more months, as per the company presentation. Responding patients did have blast clearances, but some of the remissions were short-lived and the cells did not persist in the system, said Sallman. However, the short hairpin (sh) ribonucleic acid (RNA) technology employed CYAD-02, which could increase persistence and expansion, said Sallman (Fontaine et al., [2019]Blood, 134[Suppl 1], p. 3931). ShRNA technology allows T cell engineering without the need for gene editing to inhibit alloreactivity and increase persistence, according to Celyad.

Ongoing research on improving preconditioning regimens by combining additional drugs could also help with the persistence of allogeneic products, said Davila. It is not known whether every dose needs a conditioning regimen, but since conditioning regimens can suppress a patients immune system for several months, it may not be necessary before every therapy infusion, he added.

Patients will not have to receive a preconditioning regimen before every cell infusion, said Wolchko, adding redosing FT500 was found to be safe. Celyads protocol does not specify the preconditioning strategy for redosing. No predictive biomarkers are available to explain why some patients respond well and others do not, said Sallman, adding it is critical to identify potential responders. Nonetheless, there is no way to predict clinical efficacy based only on preclinical data, so data is still needed, said Miller.

The economic advantage to developing off-the-shelf therapies has driven interest in NK-cell based platforms, said Miller and Davila. If quick treatment is needed, then an allogeneic NK cell therapy would be better than an autologous therapy, which may take up to six weeks to manufacture, said Sallman. While the results with autologous CAR T-cell therapies have been significant, their scale-up and costs are challenging, said Kaufman. Related Report

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The ability to use induced pluripotent stem cell (iPSCs) or cord blood cells as a source would help scale up the cell manufacture and allow effective results, said Kaufman. iPSCs provide advancement in expansion protocols, which can provide multiple doses, Miller added. Fate Therapeutics has an iPSC-derived NK cell franchise. Also, since T cell therapies require donor apheresis to collect cells in a process lasting four to five hours, it is not feasible to keep going back to the same donor, said Miller.

Moreover, newer platforms are expected to improve on past NK cell therapy trials, specifically those showing mixed efficacy. Past studies had feasibility limitations in getting the required number of cells, said Miller. Those small studies were conducted at a time when cell isolation and production systems were not as advanced as they are now, said Davila.

Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalDatas investigative journalism team. A version of this article originally appeared on the Insights module of GlobalDatas Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.

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Fate Therapeutics' and Celyad's CAR therapies in oncology offer potential - pharmaceutical-technology.com

LOS ANGELES--(BUSINESS WIRE)--Glancy Prongay & Murray LLP (GPM) reminds investors of the upcoming December 7, 2020 deadline to file a lead plaintiff motion in the class action filed on behalf of investors who purchased or otherwise acquired Mesoblast Limited (Mesoblast or the Company) (NASDAQ: MESO) securities between April 16, 2019 and October 1, 2020, inclusive (the Class Period).

If you suffered a loss on your Mesoblast investments or would like to inquire about potentially pursuing claims to recover your loss under the federal securities laws, you can submit your contact information at https://www.glancylaw.com/cases/mesoblast-limited/. You can also contact Charles H. Linehan, of GPM at 310-201-9150, Toll-Free at 888-773-9224, or via email at shareholders@glancylaw.com to learn more about your rights.

Mesoblast develops allogeneic cellular medicines using its proprietary mesenchymal lineage cell therapy platform. Its lead product candidate, RYONCIL (remestemcel-L), is an investigational therapy comprising mesenchymal stem cells derived from bone marrow. In February 2018, the Company announced that remestemcel-L met its primary endpoint in a Phase 3 trial to treat children with steroid refractory acute graft versus host disease (aGVHD).

In early 2020, Mesoblast completed its rolling submission of its Biologics License Application (BLA) with the FDA to secure marketing authorization to commercialize remestemcel-L for children with steroid refractory aGVHD.

On August 11, 2020, the FDA released briefing materials for its Oncologic Drugs Advisory Committee (ODAC) meeting to be held on August 13, 2020. Therein, the FDA stated that Mesoblast provided post hoc analyses of other studies to further establish the appropriateness of 45% as the null Day-28 ORR for its primary endpoint. The briefing materials stated that, due to design differences between these historical studies and Mesoblasts submitted study, it is unclear that these study results are relevant to the proposed indication.

On this news, the Companys share price fell $6.09, or approximately 35%, to close at $11.33 per share on August 11, 2020, on unusually heavy trading volume.

On October 1, 2020, Mesoblast disclosed that it had received a Complete Response Letter (CRL) from the FDA regarding its marketing application for remestemcel-L for treatment of SR-aGVHD in pediatric patients. According to the CRL, the FDA recommended that the Company conduct at least one additional randomized, controlled study in adults and/or children to provide further evidence of the effectiveness of remestemcel-L for SR-aGVHD. The CRL also identified a need for further scientific rationale to demonstrate the relationship of potency measurements to the products biologic activity.

On this news, the Companys stock fell $6.56, or 35%, to close at $12.03 per share on October 2, 2020, on unusually heavy trading volume.

The complaint filed in this class action alleges that throughout the Class Period, Defendants made materially false and/or misleading statements, as well as failed to disclose material adverse facts about the Companys business, operations, and prospects. Specifically, Defendants failed to disclose to investors: (1) that comparative analyses between Mesoblasts Phase 3 trial and three historical studies did not support the effectiveness of remestemcel-L for steroid refractory aGVHD due to design differences between the four studies; (2) that, as a result, the FDA was reasonably likely to require further clinical studies; (3) that, as a result, the commercialization of remestemcel-L in the U.S. was likely to be delayed; and (4) that, as a result of the foregoing, Defendants positive statements about the Companys business, operations, and prospects were materially misleading and/or lacked a reasonable basis.

Follow us for updates on LinkedIn, Twitter, or Facebook.

If you purchasedor otherwise acquired Mesoblast securities during the Class Period,you may move the Court no later thanDecember 7, 2020 to ask the Court to appoint you as lead plaintiff. To be a member of the Class you need not take any action at this time; you may retain counsel of your choice or take noaction and remain an absent member of the Class. If you wish tolearn moreabout this action, or if you have any questions concerning this announcement or your rights or interests with respect to these matters, please contactCharlesLinehan, Esquire, of GPM, 1925 Century Park East, Suite 2100, Los Angeles California 90067 at 310-201-9150, Toll-Free at 888-773-9224, by email toshareholders@glancylaw.com, or visit our website atwww.glancylaw.com. If you inquire by email please include your mailing address, telephone number and number of shares purchased.

This press release may be considered Attorney Advertising in some jurisdictions under the applicable law and ethical rules.

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Glancy Prongay & Murray LLP Reminds Investors of Looming Deadline in the Class Action Lawsuit Against Mesoblast Limited (MESO) - Business Wire

I am a clinical immunologist that happens to also be a stem cell scientist with 45 years of experience. The first CD34 bone marrow transplantation in 1978 was done at Roswell Park using FACS flow cytometry. We watch GvHD take hold to many leukemia patients to these brave patients trying to save their life with no way to treat them, until now with MSC (mesenchymal stem cells).

I watched many patients give their lives to science research for a chance of cures, which we had successes 40 years forward, if you get CML, CLL you have 98% of treatment or cure. CAR T and other treatments etc.

My concerns (are that) the media is presenting a perspective in vacuum of the stem cell world in California. Prop 71 put California in play and pushed embryonic research. The people of California need to protect their investment of $3.3 billion, or the industry leadership will be lost along with the clinical trials supported by CIRM. Please do not underestimate the RPE for blindness. #1 unmet medical need when the Japanese pharma Astellas bought Ocata in 2015 and put it on the shelf setting back embryonic research.

Lets look at say, Mesoblast, a Australian stem cell company and the leader in field with four studies. (They) had a setback recently of their BLA of SR aGvHD for kids under 12 years old (which is a death sentence) using MSC stem cells (approved for treatment in Japan for two years now) on the first stem cells for regenerative medicine to be approved the FDA, on Sept. 30, 2020. Mesoblast has 330 double blind studies for Covid19 treatment.

We will know before Christmas if FDA will approve these cells. MSC will be better than vaccinations, with super antigens stimulating the immune memory cells being develop by many companies and Federal government.

Two points: federal funding for embryonic research is not very well supported, and you cannot put a price tag on the patients who are willing to put their life on the line for hope and a chance.

Stay in the game California - do not be shortsighted.

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Yes on 14 | Mailbox | independentnews.com - Livermore Independent

Indias first saviour sibling experiment is a success, say doctors.

A one-year-old sibling has saved her brothers life by donating her bone marrow. Kavya was conceived by her parents through invitro fertilisation to save her brother, Abhijeet Solanki, who was born with Thalassemia.

Thalassemia is a disorder where the haemoglobin count is low in blood and such persons require frequent blood transfusions.

Abhijeet was born in November 2013 but unlike normal babies he did not achieve the growth milestones. The parents learned that Abhijeet had Thalassemia major. Abhijeet required blood transfusions every 25 days and the gap between two transfusions reduced as he grew. By the age of six Abhijeet had undergone 80 transfusions, recalled his father Sahdev Singh Solanki. The only way to save him was through a bone marrow transplant.

The family was willing to donate their bone marrow but the human leukocyte antigen (HLA) of the family, including that of his older sister, did not match.

The Solanki family consulted many doctors. Mr. Solankis research led him to the saviour sibling concept following which he sought out Manish Banker, medical director of Nova IVF Fertility in Ahmedabad.

Dr. Banker said Mr. Solankis research and the science behind it was known but nobody had approached him with such a request before.

Dr. Banker started the assisted reproductive therapy, called pre-implantation genetic testing, for monogenic disorder with HLA matching. The couple underwent three cycles of IVF and 18 embryos were created. Of this only one perfectly matched Abhijeets HLA. The embryo was implanted in Apla Solanki, who delivered a baby girl a year ago.

We had to wait for the baby to grow. She had to weigh 10 kg before we could draw bone marrow, said Deepa Trivedi, programme director of Sankalp Bone Marrow Unit, CIMS Hospital, Ahmedabad.

Pointing out that the best therapeutic option for Thalassemia major patients is bone marrow transplant from an HLA-identical donor, Dr. Banker said, We are extremely thrilled to be part of reproductive history in India to create the first-ever saviour-sibling through ART. We used pre-genetic diagnosis and screening test, an established method for conceiving a child who may donate cord blood or hematopoietic stem cells for transplantation to save a critically ill sibling.

Mr. Solanki said the transplant was done on March 17. Since then Abhijeet has not needed any blood transfusion, indicating that he had been cured of the disorder. His haemoglobin count was 11.3, Dr. Trivedi said.

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A sister born to save ailing brother - The Hindu

Every 20 minutes someone in the UK is diagnosed with blood cancer and the register of stem cell donors who are needed to save thousands of patients lives does not currently meet the demand. Only 1 in 3 patients will find a donor match within their family and so every year over 2,000 people in the UK are left searching for a matching blood stem cell donor each year.

Blood cancer patients from Black, Asian or minority ethnicity groups face lower survival odds due to the lack ofdonordiversity. These patients have just a 20% chance of finding the best possible stem cell donor match, compared to 69% for northern European backgrounds.

This is due in part to the low numbers of donors registered from those Black, Asian or ethnic minority backgrounds. Donors from minority ethnic backgrounds make up just 13.1% of the UK stem cell register and because Black, Asian or ethnic minority patients tend to have more varied tissue meaning there is an even more specific biological requirement needed of a donor than for a white patient.

The global pandemic has made this situation even worse. Only 2% of stem cell registrations with DKMS came from black people during lockdown, falling by 20% compared to the same time the previous year.

Vaughn Scott is a patient who received a lifesaving donation from a stranger.

Vaughn Scott (34 years old) lives in Bristol and is grateful to the generous stranger who helped save his life. Theyve given him more time with his two children and the chance to marry his now wife last summer in a beautiful ceremony. Vaughn was incredibly fit and active, playing all kinds of sports and serving in the Navy. It was whilst on deployment across the world that he was urgently flown back to the UK and shockingly diagnosed with acute lymphoblastic leukaemia (ALL).

Vaughn said:

Hearing the diagnosis was the biggest blow Ive ever heard. My mind raced straight to my children and partner. When we learnt there was a way I could go into remission, I was excited that there was a way I could get better but very nervous too. With no family members as a match, all my faith was in a complete stranger that may have registered as a potential stem cell donor. Thankfully my match was found, Im now married and enjoying life with my family and Im so grateful. So many people arent as lucky as me. If you can, please register and give other people the second chance at life that I have been given.

To request a swab kit and register as a potential donor click HERE.

About blood cancer

Blood cancer is the third most common cause of cancer death in the UK but there is a lot of fear around stem cell donation of the process itself and of having a depleted supply of stem cells. This isnt the case. After donation, stem cells regenerate within 2 weeks so the donor wont lose anything. Blood stem cell donation is easy to do and similar to blood donation. Around 90% of all donations are made through a method called peripheral blood stem cell (PBSC). In this method, blood is taken from one of the donors arms and a machine extracts the blood stem cells from it. The donors blood is then returned to them through their other arm. This is an outpatient procedure that is usually completed in 4-6 hours. In just 10% of cases, donations are made through bone marrow collection. This is under general anaesthetic so that no pain is experienced.

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Black History Month The struggle to find a lifesaving stem cell donor - Keep the Faith

Glancy Prongay & Murray LLP ("GPM") reminds investors of the upcoming December 7, 2020 deadline to file a lead plaintiff motion in the class action filed on behalf of investors who purchased or otherwise acquired Mesoblast Limited ("Mesoblast" or the "Company") (NASDAQ: MESO) securities between April 16, 2019 and October 1, 2020, inclusive (the "Class Period").

If you suffered a loss on your Mesoblast investments or would like to inquire about potentially pursuing claims to recover your loss under the federal securities laws, you can submit your contact information at https://www.glancylaw.com/cases/mesoblast-limited/. You can also contact Charles H. Linehan, of GPM at 310-201-9150, Toll-Free at 888-773-9224, or via email at shareholders@glancylaw.com to learn more about your rights.

Mesoblast develops allogeneic cellular medicines using its proprietary mesenchymal lineage cell therapy platform. Its lead product candidate, RYONCIL (remestemcel-L), is an investigational therapy comprising mesenchymal stem cells derived from bone marrow. In February 2018, the Company announced that remestemcel-L met its primary endpoint in a Phase 3 trial to treat children with steroid refractory acute graft versus host disease ("aGVHD").

In early 2020, Mesoblast completed its rolling submission of its Biologics License Application ("BLA") with the FDA to secure marketing authorization to commercialize remestemcel-L for children with steroid refractory aGVHD.

On August 11, 2020, the FDA released briefing materials for its Oncologic Drugs Advisory Committee ("ODAC") meeting to be held on August 13, 2020. Therein, the FDA stated that Mesoblast provided post hoc analyses of other studies "to further establish the appropriateness of 45% as the null Day-28 ORR" for its primary endpoint. The briefing materials stated that, due to design differences between these historical studies and Mesoblasts submitted study, "it is unclear that these study results are relevant to the proposed indication."

Story continues

On this news, the Companys share price fell $6.09, or approximately 35%, to close at $11.33 per share on August 11, 2020, on unusually heavy trading volume.

On October 1, 2020, Mesoblast disclosed that it had received a Complete Response Letter ("CRL") from the FDA regarding its marketing application for remestemcel-L for treatment of SR-aGVHD in pediatric patients. According to the CRL, the FDA recommended that the Company "conduct at least one additional randomized, controlled study in adults and/or children to provide further evidence of the effectiveness of remestemcel-L for SR-aGVHD." The CRL also "identified a need for further scientific rationale to demonstrate the relationship of potency measurements to the products biologic activity."

On this news, the Companys stock fell $6.56, or 35%, to close at $12.03 per share on October 2, 2020, on unusually heavy trading volume.

The complaint filed in this class action alleges that throughout the Class Period, Defendants made materially false and/or misleading statements, as well as failed to disclose material adverse facts about the Companys business, operations, and prospects. Specifically, Defendants failed to disclose to investors: (1) that comparative analyses between Mesoblasts Phase 3 trial and three historical studies did not support the effectiveness of remestemcel-L for steroid refractory aGVHD due to design differences between the four studies; (2) that, as a result, the FDA was reasonably likely to require further clinical studies; (3) that, as a result, the commercialization of remestemcel-L in the U.S. was likely to be delayed; and (4) that, as a result of the foregoing, Defendants positive statements about the Companys business, operations, and prospects were materially misleading and/or lacked a reasonable basis.

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If you purchased or otherwise acquired Mesoblast securities during the Class Period, you may move the Court no later than December 7, 2020 to ask the Court to appoint you as lead plaintiff. To be a member of the Class you need not take any action at this time; you may retain counsel of your choice or take no action and remain an absent member of the Class. If you wish to learn more about this action, or if you have any questions concerning this announcement or your rights or interests with respect to these matters, please contact Charles Linehan, Esquire, of GPM, 1925 Century Park East, Suite 2100, Los Angeles California 90067 at 310-201-9150, Toll-Free at 888-773-9224, by email to shareholders@glancylaw.com, or visit our website at http://www.glancylaw.com. If you inquire by email please include your mailing address, telephone number and number of shares purchased.

This press release may be considered Attorney Advertising in some jurisdictions under the applicable law and ethical rules.

View source version on businesswire.com: https://www.businesswire.com/news/home/20201015005282/en/

Contacts

Glancy Prongay & Murray LLP, Los AngelesCharles H. Linehan, 310-201-9150 or 888-773-92241925 Century Park East, Suite 2100Los Angeles, CA 90067www.glancylaw.com shareholders@glancylaw.com

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Glancy Prongay & Murray LLP Reminds Investors of Looming Deadline in the Class Action Lawsuit Against Mesoblast Limited (MESO) - Yahoo Finance

HAIFA, Israel, Oct. 13, 2020 (GLOBE NEWSWIRE) -- Pluristem Therapeutics Inc. (Nasdaq:PSTI) (TASE:PSTI), a leading regenerative medicine company developing a platform of novel biological products, today announced that it has received clearance from the safety committee of an investigator initiated Phase I/II study to move forward with patient enrollment for cohort II. The study will evaluate PLX-PAD cells in the treatment of steroid-refractory chronic graft vs. host disease (GvHD) and is led by Principal Investigator Prof. Ron Ram, Director of the Hematology Blood and Marrow Stem Cell Transplantation Unit at Tel Aviv Sourasky Medical Center, Ichilov Hospital, Israel. Prof. Ram and his research staff are responsible for the design and implementation of the study at Sourasky Medical Center.

GvHD is a severe complication in patients who have undergone an allogeneic hematopoietic cell transplantation (HCT) and is a major cause of morbidity and mortality in these patients in which the donated stem cells identify the recipient's body as foreign and attack it. The chronic form of GvHD (cGvHD) usually appears later than 100 days post-transplant.

Cohort I included 6 patients treated with 2 injections of 150 million cells, a week apart. At the 3-month follow up, interim safety results concluded that PLX-PAD cells were safe and that no treatment related side effects were reported. Efficacy results demonstrated that 4 out of the 6 patients reported improvement in symptoms that translated into a reduction in the severity of cGvHD with notable reduction in the required steroid doses for part of the patients. Based on these results, the study was approved to commence enrollment of 14 patients in cohort II to be treated with 4 injections of 150 million cells.

Prof. Ram of Ichilov Hospital commented, From our experience in having treated 6 patients in the study to date, we have so far found no negative side effects from the use of the PLX-PAD cells in the treatment of steroid-refractory cGvHD. Patients with significant GvHD skin disorders previously unresponsive to multiple types of therapy showed remarkable response. Responses were also observed for severe mouth ulcers which prevented patients from eating solid foods. This resulted in a major improvement of quality of life and tapering of steroid doses."

Pluristem is committed to contributing to the wellbeing and quality of life of our patients. cGvHD is an indication where we see a significant need to enhance the current course of treatment for this life-threatening condition among patients undergoing bone marrow transplants. The preliminary results from cohort I of this Phase I/II study, and prior preclinical data, both indicate that PLX-PAD cells may potentially treat cGvHD patients and mitigate symptoms. We are very pleased to cooperate with Prof. Ram and Sourasky Medical Center, and we place a high importance in examining PLX-PAD for this indication, stated Pluristem CEO and President, Yaky Yanay.

About cGvHDChronic graft-versus-host disease (cGvHD) remains a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HCT). The 2-year cumulative incidence of chronic GvHD requiring systemic treatment is 30% to 40% by National Institutes of Health criteria1. The hematopoietic stem cell transplants are used to treat bone marrow failure resulting from treatment of some blood or bone marrow cancers as well as other hematologic failures, such as aplastic anemia, which are not related to cancer. The donated cells identify the recipients body as foreign and attack it as a result. While acute GvHD usually appears in the first 100 days after a transplant, and in specific body systems, chronic GvHD can occur at any time (even several years) after a transplant, and may manifest in many parts of the body such as: skin, mouth, eyes, liver, intestines, lungs and joints. Long term immunosuppression is given to try to prevent or treat cGvHD. Since this treatment suppresses the immune system for a very long time, patients are at high risk of infections, and are prescribed multiple medications to try to address this major risk.

About Pluristem TherapeuticsPluristem Therapeutics Inc. is a leading regenerative medicine company developing novel placenta-based cell therapy product candidates. The Company has reported robust clinical trial data in multiple indications for its patented PLX cell product candidates and is currently conducting late stage clinical trials in several indications. PLX cell product candidates are believed to release a range of therapeutic proteins in response to inflammation, ischemia, muscle trauma, hematological disorders and radiation damage. The cells are grown using the Company's proprietary three-dimensional expansion technology and can be administered to patients off-the-shelf, without tissue matching. Pluristem has a strong intellectual property position; a Company-owned and operated GMP-certified manufacturing and research facility; strategic relationships with major research institutions; and a seasoned management team.

Safe Harbor StatementThis press release contains express or implied forward-looking statements within the Private Securities Litigation Reform Act of 1995 and other U.S. Federal securities laws. For example, Pluristem is using forward-looking statements when it discusses the patient enrollment for cohort II for its Phase I/II study of its PLX-PAD cells, the implication from the results of the first patient cohort in the study, the belief that GvHD is an indication that has a significant need for enhanced treatments among patients undergoing bone marrow transplants and that the preliminary results from cohort I of the study, and the prior preclinical data, indicate that PLX-PAD cells may potentially treat chronic GvHD patients and mitigate symptoms. These forward-looking statements and their implications are based on the current expectations of the management of Pluristem only, and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. The following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: changes in technology and market requirements; Pluristem may encounter delays or obstacles in launching and/or successfully completing its clinical trials; Pluristems products may not be approved by regulatory agencies, Pluristems technology may not be validated as it progresses further and its methods may not be accepted by the scientific community; Pluristem may be unable to retain or attract key employees whose knowledge is essential to the development of its products; unforeseen scientific difficulties may develop with Pluristems process; Pluristems products may wind up being more expensive than it anticipates; results in the laboratory may not translate to equally good results in real clinical settings; results of preclinical studies may not correlate with the results of human clinical trials; Pluristems patents may not be sufficient; Pluristems products may harm recipients; changes in legislation may adversely impact Pluristem; inability to timely develop and introduce new technologies, products and applications; loss of market share and pressure on pricing resulting from competition, which could cause the actual results or performance of Pluristem to differ materially from those contemplated in such forward-looking statements. Except as otherwise required by law, Pluristem undertakes no obligation to publicly release any revisions to these forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. For a more detailed description of the risks and uncertainties affecting Pluristem, reference is made to Pluristem's reports filed from time to time with the Securities and Exchange Commission.

Contact:

Dana RubinDirector of Investor Relations972-74-7107194danar@pluristem.com

_________________________________

1 Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015 Jan 22;125(4):606-15. doi: 10.1182/blood-2014-08-551994. Epub 2014 Nov 14. PMID: 25398933; PMCID: PMC4304105., https://pubmed.ncbi.nlm.nih.gov/25398933/

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Pluristem Announces Clearance to Move Forward with Enrollment for Cohort II in an Investigator-Led Phase I/II Chronic Graft vs Host Disease...

Gosselies, Belgium, 14 October 2020, 7am CEST BONE THERAPEUTICS(Euronext Brussels and Paris: BOTHE), the cell therapy company addressing unmet medical needs in orthopedics and other diseases, today announces positive 24-month follow-up results for the Phase IIa study with the allogeneic cell therapy product, ALLOB, in patients undergoing lumbar spinal fusion procedures.

The 24-month data show a high percentage of successful lumbar vertebrae fusion of 90%. Patients also continue to experience important clinical improvements in function and pain, from as early as six months after treatment, up to the 24-month follow-up period.

Degenerative spine disorders have a major impact on the quality of life of patients. These impacts include decreases in the stability of the spine and pain in motion,said Dr. Alphonse Lubansu, M.D., Head of the Spinal Clinic, Erasme University Hospital, Universit libre de Bruxelles. The 24 month follow-up data of this Phase IIa clinical trial have demonstrated that patients treated with ALLOB in spinal fusion procedure show a high incidence in fusion, and benefit from a sustained, clinically meaningful improvement in function and pain throughout the 24 months following treatment together with a good safety profile. These results show that ALLOB in combination with the standard spine fusion surgery could be a promising treatment option to address the currently unmet needs of these patients.

This positive data forlumbar spinal fusion complementsthe strong Phase I/IIa results from ALLOB in patients with delayed union fractures,said Miguel Forte, MD, PhD, Chief Executive Officer of Bone Therapeutics. These studies provide promising clinical evidence for the potential ofBone Therapeuticsunique allogeneic cell therapy platform to address high unmet medical needs in orthopaedics and bone related disorders. We will now hold discussions with global regulators and our partners to explore a variety of options for the next stages of clinical development for ALLOB in different orthopedic indications, while pursuing the phase IIb study of ALLOB in difficult tibial fractures.In addition, theclinical results provide further evidence for the expansion of ALLOB and our platform of differentiated MSCs to other indications.

The multi-center, open-label proof-of-concept Phase IIa study was designed to evaluate the safety and efficacy of ALLOB administered, procedure in which an interbody cage with bioceramic granules mixed with ALLOB is implanted into the spine to achieve fusion of the lumbar vertebrae. The main endpoints of the 24-month follow-up analysis included safety and radiological assessments to evaluate vertebrae fusion (continuous bone bridges) and clinical assessments to evaluate improvement in patients functional disability as well as reduction in back and leg pain. The study evaluated 30 patients treated with ALLOB, 29 patients attended the 24-month visit.

Radiological data was collected from CT-scans at 24 months and assessed by three external readers. It showed a successful fusion of the lumbar vertebrae in 27 out of 30 patients (90%). In addition, the remaining 3 patients showed radiological evidence of bone formation. Treatment with ALLOB also resulted in a clear and statistically significant clinical improvement in function and reduction in pain over the 24-month follow-up period. Functional disability improved from the pre-treatment baseline to 24-month by a mean score of 60% (p<0.001) on the Oswestry Disability Index(1). Back and leg pain were strongly reduced by 57 to 62% (p<0.001) and 68 to 70% (p<0.001) respectively compared to pre-treatment baseline. Treatment with ALLOB was generally well-tolerated by the patients, consistent with previous reported results.

(1)The Oswestry Disability Index (ODI) is an index derived from the Oswestry Low Back Pain Questionnaire used by clinicians and researchers to measure a patients permanent functional disability. This validated questionnaire was first published by Jeremy Fairbank et al. in Physiotherapy in 1980. ODI score of 0%-20%: minimal disability; 21%-40%: moderate disability; 41%-60%: severe disability; 61%-80%: crippled; 81%-100%: bed bound.

About Spinal Fusion

Due to ageing populations and sedentary lifestyles, the number of people suffering from degenerative spine disorders continues to increase. Today, spinal fusion procedures are performed to relieve pain and improve patient daily functioning in a broad spectrum of degenerative spine disorders. Spinal fusion consists of bridging two or more vertebrae with the use of a cage and graft material, traditionally autologous bone graft or demineralised bone matrix placed into the intervertebral space for fusing an unstable portion of the spine and immobilizing a painful intervertebral motion segment. Over 1,000,000 spinal fusion procedures are performed annually in the US and EU, of which half at lumbar level and the market is growing at a rate of 5% per year. Although spinal fusion surgery is routine, non-fusion, slow progression to fusion and failure to eliminate pain are still frequent with up to 35% of patients not being satisfied with their surgery.

About ALLOB

ALLOB is the Companys off-the-shelf allogeneic cell therapy platform consisting of human allogeneic bone-forming cells derived from cultured bone marrow mesenchymal stem cells (MSC) from healthy adult donors, offering numerous advantages in product quality, injectable quantity, production, logistics and cost as compared to an autologous approach. To address critical factors for the development and commercialisation of cell therapy products, Bone Therapeutics has established a proprietary, optimised production process that improves consistency, scalability, cost effectiveness and ease of use of ALLOB. This optimized production process significantly increases the production yield, generating 100,000 of doses of ALLOB per bone marrow donation. Additionally, the final ALLOB product will be cryopreserved, enabling easy shipment and the capability to be stored in a frozen form at the hospital level. The process will therefore substantially reduce overall production costs, simplify supply chain logistics, improve patient accessibility and facilitate global commercialisation. The Company will implement the optimized production process for all future clinical trials with ALLOB.

About Bone Therapeutics

Bone Therapeutics is a leading biotech company focused on the development of innovative products to address high unmet needs in orthopedics and other diseases. The Company has a, diversified portfolio of cell and biologic therapies at different stages ranging from pre-clinical programs in immunomodulation to mid-to-late stage clinical development for orthopedic conditions, targeting markets with large unmet medical needs and limited innovation.

Bone Therapeutics is developing an off-the-shelf next-generation improved viscosupplement, JTA-004, which is currently in phase III development for the treatment of pain in knee osteoarthritis. Consisting of a unique combination of plasma proteins, hyaluronic acid a natural component of knee synovial fluid, and a fast-acting analgesic, JTA-004 intends to provide added lubrication and protection to the cartilage of the arthritic joint and to alleviate osteoarthritic pain and inflammation. Positive phase IIb efficacy results in patients with knee osteoarthritis showed a statistically significant improvement in pain relief compared to a leading viscosupplement.

Bone Therapeutics core technology is based on its cutting-edge allogeneic cell therapy platform with differentiated bone marrow sourced Mesenchymal Stromal Cells (MSCs) which can be stored at the point of use in the hospital. Currently in pre-clinical development, BT-20, the most recent product candidate from this technology, targets inflammatory conditions, while the leading investigational medicinal product, ALLOB, represents a unique, proprietary approach to bone regeneration, which turns undifferentiated stromal cells from healthy donors into bone-forming cells. These cells are produced via the Bone Therapeutics scalable manufacturing process. Following the CTA approval by regulatory authorities in Europe, the Company is ready to start the phase IIb clinical trial with ALLOB in patients with difficult tibial fractures, using its optimized production process. ALLOB continues to be evaluated for other orthopedic indications including spinal fusion, osteotomy, maxillofacial and dental.

Bone Therapeutics cell therapy products are manufactured to the highest GMP standards and are protected by a broad IP (Intellectual Property) portfolio covering ten patent families as well as knowhow. The Company is based in the BioPark in Gosselies, Belgium. Further information is available atwww.bonetherapeutics.com.

For further information, please contact:

Bone Therapeutics SAMiguel Forte, MD, PhD, Chief Executive OfficerJean-Luc Vandebroek, Chief Financial OfficerTel: +32 (0)71 12 10 00investorrelations@bonetherapeutics.com

For Belgian Media and Investor Enquiries:BepublicCatherine HaquenneTel: +32 (0)497 75 63 56catherine@bepublic.be

International Media Enquiries:Image Box CommunicationsNeil Hunter / Michelle BoxallTel: +44 (0)20 8943 4685neil.hunter@ibcomms.agency / michelle@ibcomms.agency

For French Media and Investor Enquiries:NewCap Investor Relations & Financial CommunicationsPierre Laurent, Louis-Victor Delouvrier and Arthur RouillTel: +33 (0)1 44 71 94 94bone@newcap.eu

For US Media and Investor Enquiries:LHA Investor RelationsYvonne BriggsTel: +1 310 691 7100ybriggs@lhai.com

Certain statements, beliefs and opinions in this press release are forward-looking, which reflect the Company or, as appropriate, the Company directors current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its subsidiary undertakings or any such persons officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release.

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Bone Therapeutics' allogeneic cell therapy product, ALLOB, shows 90% fusion rate at 24 months in Phase IIa study in lumbar spinal fusion -...

Building on the transformative impetus from the first Food and Drug Administration (FDA)-approved Janus kinase (JAK) 1/2 inhibitor, ruxolitinib (Jakafi), in the clinical landscape of myeloproliferative neoplasms (MPNs), we are entering a new era of multiple JAK inhibitors and other diverse classes of drugs in rapid clinical development. Advancements in elucidating the pathophysiology of MPNs have spurred significant progress in developing novel promising agents or combination regimens with ruxolitinib to treat patients who are unresponsive to standard treatments or have specific clinical needs.

In myelofibrosis (MF), the most aggressive MPN, with an average survival of 5 to 7 years, abnormal clonal hematopoietic stem cell proliferation in the bone marrow (BM) leads to liberation of pro-inflammatory cytokines and extensive fibrosis, causing progressive pancytopenia, especially anemia and thrombocytopenia, along with splenomegaly and other symptoms, compromising quality of life.1

For nearly a decade, ruxolitinib has been the centerpiece therapy for patients with MF, markedly improving splenomegaly and constitutional symptoms and providing survival benefit.2 The second FDA-approved JAK2 inhibitor, fedratinib (Inrebic), may actually be a good second-line option for patients who are ruxolitinib-resistant with intermediate-2 and high-risk MF (primarily thrombocytopenic and characterized by platelet counts 50100 109/L).3 At present, 2 ongoing phase 3 clinical trials, the single-arm FREEDOM trial (NCT03755518) and the double-arm FREEDOM 2 trial (NCT03952039), are assessing the efficacy and safety of fedratinib in patients with MF who are resistant/refractory/intolerant to ruxolitinib. The FREEDOM trials are important because the previous JAKARTA studies (NCT01523171, NCT01437787) were placed on hold or terminated given concerns for the development of Wernicke encephalopathy. Pacritinib is a potent inhibitor of both JAK2 and fms-related receptor tyrosine kinase

3, or FLT3, but does not affect JAK1. Pacritinib is being evaluated in comparison with the physicians choice in an ongoing phase 3 trial (PACIFICA; NCT03165734) in patients with MF and severe thrombocytopenia (baseline platelet count < 50 109/L) at the optimal dose determined in the PAC203 study (200 mg twice daily; NCT03165734).3 Successful clinical development of pacritinib will provide a non-myelosuppressive JAK2 inhibitor for frontline treatment of patients with MF who have severe thrombocytopenia, a setting currently lacking approved drugs. Another JAK1/2 inhibitor that is in advanced clinical development and complements its predecessors is momelotinib, possessing the exclusive attribute to improve anemia, which becomes severe in patients with MF.3 At present, momelotinib is undergoing evaluation in patients who are symptomatic and anemic with advanced MF, previously treated with a JAK inhibitor, in a phase 3 trial (MOMENTUM; NCT04173494); the comparator drug is danazol.

Targeting anemia and thrombocytopenia. Given that patients with MF experience disease-associated and JAK inhibitor-induced anemia, several clinical trials have been evaluating drugs counteracting anemia, as monotherapies or in combination with ruxolitinib, in patients with MF-associated anemia.4 Currently, a global, multicenter phase 2 trial is under way to evaluate the safety and efficacy of luspatercept-aamt (Reblozyl), an activin receptor ligand trap that enhances late-stage erythropoiesis in patients with anemia and MF, including ruxolitinib-treated, transfusion-dependent individuals; a phase 3 trial (INDEPENDENCE) is planned for 2020. Interim results of the phase 2 study demonstrated significant efficacy of luspatercept-aamt, achieving reduction in red blood cell transfusion burden in ruxolitinib-treated patients with MF. Thalidomide (Thalomid), an immunomodulatory agent, significantly improved anemia and thrombocytopenia (platelet counts increased in 60% of patients) in a phase 2 trial evaluating ruxolitinib-treated patients with MF and baseline thrombocytopenia (NCT03069326).5

Synergistic combinations with ruxolitinib targeting epigenetics and JAK2 (TABLE). CPI-0610 is a selective bromodomain and extraterminal protein inhibitor that improved spleen volume, anemia, BM fibrosis, total symptom score, and transfusion dependence (alone or with ruxolitinib) in patients with MF who are enrolled in the global phase 2 MANIFEST study (NCT02158858).3 Furthermore, a phase 1 clinical trial combining an inhibitor of heat shock protein 90 (JAK2 is its chaperone protein), PU-H71, with ruxolitinib in patients with primary/secondary MF is under way (NCT03935555).3 The previous 2 trials are supported by preclinical data showing drug synergism. In a phase 2 trial of ruxolitinib/azacitidine (hypomethylating agent) in patients with MF, synergism was demonstrated in spleen length reduction and BM fibrosis improvement compared with ruxolitinib monotherapy (NCT01787487).5

Synergistic combinations with ruxolitinib targeting antiapoptotic proteins and JAK2. Navitoclax is an orally bioavailable inhibitor of the antiapoptotic B-cell lymphoma 2 (BCL2) family of proteins (primarily BCL extra-large [XL]). In preclinical studies, the nonclinical analogue of navitoclax, ABT-737, in combination with ruxolitinib showed synergism in inducing apoptosis of JAK2 V617F-driven MPN cell lines. Interim data from an ongoing phase 2 clinical trial evaluating navitoclax in combination with ruxolitinib in ruxolitinib-treated patients with MF (with baseline platelet count 100 109/L) showed reduction in spleen volume and BM fibrosis (1 grade) and improvement in total symptom score in a proportion of the patients (NCT03222609).3

Imetelstat is a short oligonucleotide telomerase inhibitor that possibly prolonged median overall survival in patients with MF in the higher-dose (9.4-mg/kg) arm of the phase 2 IMbark study (NCT02426086).3 A phase 3 trial comparing imetelstat to best available therapy in patients with refractory MF is planned for early 2021.

PRM-151, a plasma-derived analogue of the human antifibrotic protein pentraxin 2, improved BM fibrosis in mice models and patients with MF in preclinical and phase 1/2 clinical studies, respectively.3 The promising results merit a phase 3 trial, especially given the scarcity of antifibrotic agents.

The two relatively indolent MPN subtypes, polycythemia vera (PV) and essential thrombocythemia (ET), are characterized by abnorabnormal proliferation of myeloid cells, resulting in elevated blood counts (erythrocytosis and thrombocytosis in PV and ET, respectively), considerable risk of thrombosis and hemorrhage, and progression to secondary MF and acute myeloid leukemia (more common in PV than ET).6 In PV and ET, therapies are aimed at reducing risk of thrombosis, which is higher in patients over 60 years old or with a history of thrombosis, and in ET, when the calreticulin gene, CALR, is absent. A particularly promising agent for the two indolent MPNs is the long-acting ropeginterferon -2b, which was approved in Europe for frontline treatment of high-risk patients with PV and without symptomatic splenomegaly on the basis of the PROUD/CONTINUATION-PV studies [EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357- 17 (CONTINUATION-PV)].7 The previous investigations demonstrated superiority of ropeginterferon -2b versus hydroxyurea after 3 years of therapy. Besides awaiting possible approval of ropeginterferon -2b to treat patients with PV in the United States, a phase 3 trial of ropeginterferon -2b versus anagrelide in hydroxyurea-resistant/intolerant patients with ET has been planned to start in 2020. Givinostat, an inhibitor of histone deacetylases, demonstrated promising clinical responses (reduction in pruritus and thrombosis, and normalization of hematological parameters) in phase 1/2 studies in patients with JAK2 V617F positive PV and is entering a phase 3 trial in 2021.7 Currently, hydroxyurea and ruxolitinib are the first- and second-line treatments for high-risk patients with PV, respectively, and hydroxyurea is the first-line treatment for ET.

Herein we highlighted an array of drugs ranging from new JAK inhibitors to an antifibrotic agent, epigenetic modifiers, and telomerase and BCL-XL/BCL2 inhibitorsthat are in early or advanced clinical development in MPN. We are looking forward to enrichment of the MPN arsenal with new disease-modifying agents complementing the clinical benefits of ruxolitinib and fulfilling unmet needs in this population.

References:

1. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. doi:10.1186/s13045-017-0527-7

2. Bose P, Verstovsek S. Management of myelofibrosis after ruxolitinib failure. Leuk Lymphoma. Published online April 16, 2020. doi:10.1080/1 0428194.2020.1749606

3. Bose P, Verstovsek S. Management of myelofibrosis-related cytopenias. Curr Hematol Malig Rep. 2018;13(3):164-172. doi:10.1007/s11899- 018-0447-9

3. Bose P, Alfayez M, Verstovsek S. New concepts of treatment for patients with myelofibrosis. Curr Treat Options Oncol. 2019;20(1):5. doi:10.1007/s11864-019-0604-y

4. Bose P, Verstovsek S. Updates in the management of polycythemia vera and essential thrombocythemia. Ther Adv Hematol. 2019;10:2040620719870052. doi:10.1177/2040620719870052

5. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196-e208. doi:10.1016/S2352- 3026(19)30236-4

6. Chifotides HT, Bose P, Verstovsek S. Givinostat: an emerging treatment for polycythemia vera. Expert Opin Investig Drugs. 2020;29(6):525- 536. doi:10.1080/13543784.2020.1761323

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New Therapies in Development for Myelofibrosis - Targeted Oncology