Archive for the ‘Gene Therapy Research’ Category

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PRATTELN, Switzerland I May06, 2020 I Santhera Pharmaceuticals (SIX: SANN) announces the signing of two agreements with Rutgers, The State University of New Jersey as part of its program to advance gene therapy research for the treatment of LAMA2-deficient congenital muscular dystrophy (LAMA2MD or MDC1A). Under the agreements, Santhera gains rights to intellectual property developed at Rutgers on certain gene constructs that will be further studied under a collaboration agreement.

Santhera has entered into a license agreement with Rutgers, The State University of New Jersey and a collaboration with Prof. Peter Yurchenco, a pioneer in a novel gene therapy approach for the treatment of LAMA2MD. These agreements complement the ongoing collaboration of Santhera with Prof. Markus Regg from the Biozentrum of the University of Basel [1]. Previous collaborative work by Prof. Regg and Prof. Yurchenco has established the potential of this approach in animal models.

The novel gene therapy strategy developed by these leading experts uses two linker proteins that are composed of domains derived from extracellular matrix proteins agrin, laminin and nidogen [2-5]. In animal models for LAMA2MD, this approach has led to restoration of muscle fiber basement membranes, recovery of muscle force and size, increased overall body weight and markedly prolonged survival thus demonstrating strong evidence for disease modifying potential [2].

The coordinated work of both collaborations will further advance Santheras effort to bring this innovative gene therapy approach to patients with LAMA2MD.

Gene replacement is a promising therapeutic option for the treatment of LAMA2MD, said Peter D. Yurchenco, MD, PhD, Professor at Rutgers Robert Wood Johnson Medical School, USA. We have been working on continuously optimizing linker proteins engineered from extracellular matrix proteins which will aid in advancing such gene therapy approach towards clinical use.

Santhera is excited to extend its collaborative network for this therapeutic approach, now including experts from Rutgers University, added Kristina Sjblom Nygren, MD, Chief Medical Officer and Head of Development of Santhera. This will add value to our gene therapy program for LAMA2MD and complements the work already under way with the Biozentrum at the University of Basel, which was awarded a grant by Innosuisse in 2019. Both of our collaboration partners have pioneered this field and will work closely with Santhera, clinical experts and the patient community to establish the best way to bring this approach to clinical use.

About LAMA2MD (CMD Type 1A or MDC1A) and Emerging Therapy Approaches

Congenital muscular dystrophies (CMDs) are inherited neuromuscular diseases characterized by early-onset weakness and hypotonia alongside associated dystrophic findings in muscle biopsy. Progressive muscle weakness, joint contractures and respiratory insufficiency characterize most CMDs. Laminins are proteins of the extracellular matrix that help maintain muscle fiber stability by binding to other proteins. LAMA2-related muscular dystrophy (LAMA2MD, also called MDC1A), is one of the most common forms of CMD. It is caused by mutations in the LAMA2 gene encoding the alpha2 subunit of laminin-211. Most LAMA2MD patients show complete absence of laminin-alpha 2, are hypotonic (floppy) at birth, fail to ambulate, and succumb to respiratory complications.

Previous work has demonstrated that two linker proteins, engineered with domains derived from the extracellular matrix proteins agrin, laminin and nidogen, could compensate for the lack of laminin-alpha2 and restore the muscle basement membrane [2-5]. Through simultaneous expression of artificial linkers (SEAL), this gene therapy approach aims to overcome the genetic defect by substituting laminin-alpha2 deficiency with small linker proteins containing necessary binding domains to re-establish muscle fiber integrity. In a transgenic mouse model, the linker expression increased the lifespan of LAMA2-deficient mice 5-fold to a median of 81 weeks compared to 15.5 weeks in the disease model without the therapeutic linker expression [2]. Recently, it was demonstrated that such linker constructs could be applied by standard adeno-associated virus (AAV) vectors [6, 7]. First results using the AAV technology have been presented by Prof Regg [8].

References

[1] Santhera press release on gene collaboration with Biozentrum Basel (May 21, 2019), accessible here

[2] Reinhard et al. (2017). Sci Transl Med 9, eaal4649

[3] Moll et al. (2001). Nature 413, 302-307.

[4] Meinen et al. (2007) J. Cell Biol. 176, 979-993.

[5] McKee et al. (2017) J. Clin. Invest. 127, 1075-1089.

[6] Qiao et al. (2018) Mol Ther Methods Clin Dev 9, 47-56.

[7] Qiao et al. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 11999-12004.

[8] Reinhard, J. et al. (2019) Neuromuscular Disorders, Volume 29, S164

About Rutgers, The State University of New Jersey

Rutgers, The State University of New Jersey, is a leading national research university and the state of New Jerseys preeminent, comprehensive public institution of higher education. Established in 1766, the university is the eighth-oldest higher education institution in the United States. More than 71,000 students and 23,000 faculty and staff learn, work and serve the public at Rutgers University-New Brunswick, Rutgers University-Newark, Rutgers University-Camden, and Rutgers Biomedical and Health Sciences.

About Santhera

Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative medicines for rare neuromuscular and pulmonary diseases with high unmet medical need. Santhera is building a Duchenne muscular dystrophy (DMD) product portfolio to treat patients irrespective of causative mutations, disease stage or age. A marketing authorization application for Puldysa (idebenone) is currently under review by the European Medicines Agency. Santhera has an option to license vamorolone, a first-in-class anti-inflammatory drug candidate with novel mode of action, currently investigated in a pivotal study in patients with DMD to replace standard corticosteroids. The clinical stage pipeline also includes lonodelestat (POL6014) to treat cystic fibrosis (CF) and other neutrophilic pulmonary diseases, as well as omigapil and an exploratory gene therapy approach targeting congenital muscular dystrophies. Santhera out-licensed ex-North American rights to its first approved product, Raxone (idebenone), for the treatment of Leber's hereditary optic neuropathy (LHON) to Chiesi Group. For further information, please visit http://www.santhera.com.

SOURCE: Santhera Pharmaceuticals

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Santhera Signs Agreements in Gene Therapy Research for Congenital Muscular Dystrophy with Rutgers University | More News | News Channels -...

WORCESTER, Mass., May 12, 2020 (GLOBE NEWSWIRE) -- Mustang Bio, Inc. (Mustang) (NASDAQ: MBIO), a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases, today announced two poster presentations at the virtual 23rd Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT), being held May 12-15, 2020.

Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, We are extremely pleased with the strides forward that our researchers have made in gaining greater insights into our innovative CS1 chimeric antigen receptor (CAR) T cell therapy (MB-104), which we previously licensed from City of Hope. We commend them on their poster presentations at ASGCT and look forward to learning more as they continue their research to optimize our clinical trials.

Details on the poster presentations are as follows:

Title: CS1 Targeted CAR-T Cells (MB-104) for the Treatment of Multiple Myeloma Shows Antitumor Activity Sparing Normal T-Cells Despite the Common Expression of CS1Session: Cell TherapiesAbstract number: 421Date and Time: Tuesday, May 12, 2020, 5:30 PM-6:30 PM ETRoom: Exhibit Hall C & DAuthors: Nathan Gumlaw, Aviva Joseph, James Edinger, Ekta Patel, Research and Translational Sciences, Mustang Bio, Worcester, MA

This poster describes researchers investigation into the impact of MB-104 on CS1 positive and negative cells in vitro, as well as T cells due to shared CS1 antigen expansion. The researchers demonstrated MB-104 does not confer biologically significant fratricide and can be successfully manufactured as evident by viability, growth kinetics and fold expansion, despite the shared antigen expression between tumor cells and T cells. CS1 positive T cells are present in culture during the expansion of MB-104, suggesting absence of fratricide. Finally, MB-104 can induce potent anti-tumor cell lysis and proliferates in response to tumor cells but not primary T cells expressing CS1. Taken together, their results demonstrate MB-104 is a novel CS1-targeting CAR T that shows potent anti-tumor cell lysis but spares normal T cells, despite the shared CS1 antigen expression.

Title: Development of an Immunohistochemistry Assay for the Detection of CS-1 Expression in Multiple Myeloma PatientsSession: Pharmacology/Toxicology Studies or Assay DevelopmentAbstract number: 897Date and Time: Wednesday, May 13, 2020, 5:30 PM-6:30 PM ETRoom: Exhibit Hall C & DAuthors: Bethany Biron Girard, James Edinger, Ekta Patel, Translational Sciences, Mustang Bio, Worcester, MA

This poster details a study in which researchers evaluated commercially available CS1 antibodies for IHC and identified the best clone with high specificity for CS1 to improve screening subjects for CS1 positive tumor expression prior to treatment and correlate efficacy with antigen expression. The researchers, for the first time, developed and optimized a robust immunohistochemistry assay for the assessment of CS1 expression in bone marrow core biopsy samples and plasmacytoma solid tumor samples from multiple myeloma (MM) patients, which can be used for enrollment into Mustangs CS1 CAR T clinical trials.

For more information, including abstracts, please visit the ASGCT meeting website at https://annualmeeting.asgct.org/am20/.

About Mustang BioMustang Bio, Inc. (Mustang) is a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases. Mustang aims to acquire rights to these technologies by licensing or otherwise acquiring an ownership interest, to fund research and development, and to outlicense or bring the technologies to market. Mustang has partnered with top medical institutions to advance the development of CAR T therapies across multiple cancers, as well as a lentiviral gene therapy for XSCID. Mustang is registered under the Securities Exchange Act of 1934, as amended, and files periodic reports with the U.S. Securities and Exchange Commission (SEC). Mustang was founded by Fortress Biotech, Inc. (NASDAQ: FBIO). For more information, visit http://www.mustangbio.com.

ForwardLooking Statements

This press release may contain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, each as amended. Such statements include, but are not limited to, any statements relating to our growth strategy and product development programs and any other statements that are not historical facts. Forward-looking statements are based on managements current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock value. Factors that could cause actual results to differ materially from those currently anticipated include: risks relating to our growth strategy; our ability to obtain, perform under and maintain financing and strategic agreements and relationships; risks relating to the results of research and development activities; risks relating to the timing of starting and completing clinical trials; uncertainties relating to preclinical and clinical testing; our dependence on third-party suppliers; our ability to attract, integrate and retain key personnel; the early stage of products under development; our need for substantial additional funds; government regulation; patent and intellectual property matters; competition; as well as other risks described in our SEC filings. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law.

Company Contacts:Jaclyn Jaffe and William BegienMustang Bio, Inc.(781) 652-4500ir@mustangbio.com

Investor Relations Contact:Daniel FerryLifeSci Advisors, LLC(617) 430-7576daniel@lifesciadvisors.com

Media Relations Contact:Tony Plohoros6 Degrees(908) 591-2839tplohoros@6degreespr.com

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Mustang Bio Announces Presentations at 23rd Annual Meeting of the American Society of Gene & Cell Therapy - GlobeNewswire

The latest report pertaining to The Future of Gene Therapy Market collated by Market Study Report, LLC, provides a detailed analysis regarding market size, revenue estimations and growth rate of the industry. In addition, the report illustrates the major obstacles and newest growth strategies adopted by leading manufacturers who are a part of the competitive landscape of this market.

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According to a new report, the global gene therapy market is anticipated to reach USD 4,300 million by 2021. The demand for gene therapy is primarily driven by continuous technological advancements and successful progression of several clinical trials targeting treatments with strong unmet need. Moreover, rising R&D spend on platform technologies by large and emerging biopharmaceutical companies and favorable regulatory environment will accelerate the clinical development and the commercial approval of gene therapies in the foreseeable future. Despite promise, the high cost of gene therapy represents a significant challenge for commercial adoption in the forecast period.

Gene therapy offers promise in the treatment of range of indications in cancer and genetic disorders. Large Pharmaceuticals and Biotechnology companies exhibit strong interest in this field and key among them include Allergan, Shire, Biomarin, Pfizer and GSK. The gene therapy space is witnessing a wave of partnerships and alliances. Pfizer has recently expanded its presence in gene therapy with the acquisition of Bamboo Therapeutics and Allergan entered the field, with the acquisition of RetroSense and its Phase I/II optogenetic program.

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North America holds a dominating position in the global gene therapy market which is followed by Europe and the Asia Pacific. The U.S. has maximum number of clinical trials ongoing followed by Europe. Moreover, the field of gene therapy in the U.S. and Europe continues to gain investor attention driven by success of high visible clinical programs and the potential of gene therapy to address strong unmet need with meaningful commercial opportunity. Moreover, the increasing partnerships and alliances and the disruptive potential of gene therapy bodes well for the sector through the forecast period.

Gene therapy involves inactivating a mutated gene that is not functioning properly and introducing a new gene to assist in fighting a disease. Overall, the field of gene therapy continues to mature and advance with many products in development and nearing commercialization. For instance, Spark Therapeutics received approval of Luxturna, a rare form inherited blindness in December 2017. Gene therapy market in late 2017 also witnessed the approvals of Gilead/Kite Pharmas Yescarta and Novartis Kymriah in the cancer therapeutic area.

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Key Findings from the study suggest products accessible in the market are much competitive and manufacturers are progressively concentrating on advancements to pick up an aggressive edge. Companies are in a stage of development of new items in order to guarantee simple implementation and connection with the current gene. The hospatility segment is anticipated to grow at a high growth rate over the forecast period with the expanding utilization of smart locks inferable from expanding security-related worries among clients amid their stay at the hotels. North America is presumed to dominate the global smart locks market over the forecast years and Asia Pacific region shows signs of high growth owing to the booming economies of India, and China.

The Future of Gene Therapy Market share byMajor regions included:

United StatesNorth AmericaAsia PacificEuropeMiddle East & Africa

Table of Contents

1.Gene Therapy Overview1.1.History and Evolution of Gene Therapies1.2.What is Gene Therapy1.3.Types of Gene Therapy1.4.Ex vivo and in vivo Approaches of Gene Therapy1.5.RNAi Therapeutics1.6.CAR-T Technology based Gene Therapy1.7.Types of Vectors used for Gene Therapy1.7.1.Viral1.7.2.Non-Viral2.Historical Marketed Gene Therapies [2003-2012]2.1.Rexin-G (Epeius Biotechnologies Corporation)2.2.Gendicine (SiBiono GeneTech Co., Ltd)2.3.Neovasculgen [Human Stem Cells Institute (HSCI))2.4.Glybera (UniQure Biopharma B.V.)3.First Countries to get an access to Gene Therapies3.1.Philippines for Rexin-G [2003]3.2.China for Gendicine [2003]3.3.Russia for Neovasculgen [2011]3.4.Selected European Countries for Glybera [2012]4.Marketed Gene Therapies [Approved in Recent Years]4.1.KYMRIAH (tisagenlecleucel)4.1.1.Therapy Description4.1.2.Therapy Profile4.1.2.1.Company4.1.2.2.Approval Date4.1.2.3.Mechanism of Action4.1.2.4.Researched Indication4.1.2.5.Vector Used4.1.2.6.Vector Type4.1.2.7.Technology4.1.2.8.Others Development Activities4.1.3.KYMRIAH Revenue Forecasted till 20214.2.YESCARTA (axicabtagene ciloleucel)4.2.1.Therapy Description4.2.2.Therapy Profile4.2.2.1.Company4.2.2.2.Approval Date4.2.2.3.Mechanism of Action

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Global and Regional The Future of Gene Therapy Market Research 2018 Report | Growth Forecast 2026 - Jewish Life News

MEMPHIS, Tenn. and BOTHELL, Wash., May 12, 2020 /PRNewswire/ -- Key Biologics and Astarte Biologics, together the leading provider of research- and clinical-grade human immune cells, blood products, and related services to the biopharmaceutical industry, today announced its rebranding to Cellero. The new Cellero brand better reflects the full capabilities of the organization, which serves customers across the entire cell and gene therapy lifecyclefrom concept to cure. In 2018, Key Biologics and Astarte Biologics merged to establish a comprehensive product and service offering that provides researchers critical access to biomaterial products, and the new Cellero brand represents the synergy and broad capabilities of the combined organizations.

"We are very excited to announce the launch of Cellero and the comprehensive, end-to-end product and service line we offer to our customers," said Jeffrey Allen, CEO. "Regardless of where organizations are in the continuum of discovery through cure, they can trust Cellero to recruit common and hard-to-find blood donors, isolate and characterize specific immune cells, deliver high-volume pure blood products, execute early-stage contract research and discovery projects, and collect from patients for autologous and allogeneic therapies."

In conjunction with the launch of the new brand, Cellero has also announced the grand opening of its new, state-of-the-art cell collection and CLIA-laboratory facility in Lowell, MA. The new facility, combined with the doubling of the company's capacity for collections at its Memphis site in late 2019, represent the completion of Phase One of Cellero's multi-year $50 million plan to invest in new facilities and capabilities to meet the growing demand for human cells for biopharmaceutical R&D and clinical development.

Allen continued, "Our mission is to fuel and accelerate advancements in the discovery, development, and administration of new treatments and cures. Our new facility in Lowell represents one of several steps to execute on this vision and meet the growing demand of our clinical and R&D customers for high-quality cell-based products. This new facility supports our commitment to sourcing and delivering a full range of fresh and frozen GMP-grade biomaterials to some of the most cutting-edge biopharmaceutical companies in Massachusetts, Europe, and elsewhere around the world. Even more exciting is that our new location will also provide apheresis collections for patients in the greater New England area, establishing Cellero as a critical player in the local community supporting patients receiving innovative, life-changing cell therapies."

The new 5,000 square foot facility in Lowell boasts state of the art collection stations utilizing TerumoBCT Spectra Optias for optimal blood collection and superior donor/patient safety and comfort. In addition to the collection suites, a CLIA-licensed laboratory is situated onsite to ensure the highest quality, most efficient operations for Cellero's donors, patients, and customers.

With locations in Seattle, Memphis, and Lowell, Cellero is able to quickly and reliably supply fresh and frozen leukapheresis products to customers across North America, Europe, and Asia. In addition to research and clinical leukapheresis products, the company offers cell characterization and processing services to support cell therapy manufacturers as well as cell-based research tools and services for drug discovery.

Get to know Cellero!

ABOUT CELLEROCellero is the most comprehensive end-to-end provider of donor and patient collection services, biomaterials, characterized immune cells, and custom research and clinical laboratory services for companies developing new drugs and therapies.

Cellero leverages immunology research expertise and coast-to-coast collection facilities and distribution centers to service academic and biopharmaceutical researchers around the world. Visit http://www.cellero.comto learn how Cellero can be your partner in discovery and development.

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Key Biologics and Astarte Biologics Rebrand as Cellero and Announce Completion of Phase One of $50 Million Multi-Year Expansion Plan - NBC Right Now

GERMANTOWN, Md., May 11, 2020 (GLOBE NEWSWIRE) -- Orgenesis Inc. (NASDAQ: ORGS) (Orgenesis or the Company), a pioneering, global biotech company committed to accelerating commercialization and transforming the delivery of cell and gene therapies (CGTs) while lowering costs, today reported financial results for the first quarter ended March 31, 2020.

First Quarter 2020 Financial Highlights:

Vered Caplan, CEO of Orgenesis, commented, Step by step, our CGT Biotech Platform is gaining traction within the market, as illustrated by the year-over-year growth. In the first quarter of 2020, revenue increased to $1.9 million, or nearly an $8 million revenue run rate compared to $3.1 million for all of 2019. We believe our CGT Biotech Platform is poised for growth this year through industry partnerships that are currently underway with leading research institutes and hospitals around the world.

Earlier this year, we entered into a collaboration agreement with two of the leading healthcare research institutes in the U.S., whereby we plan to utilize our POCare Network to support their growing development and processing needs in order to advance and accelerate cell and gene-based clinical therapeutic research. We believe these collaborations with such high-profile institutions in the field of cell and gene therapy further validate the significant value proposition of our platform.

In addition to our POCare Network, we are building our pipeline of POCare Therapeutics and Technologies, with an ultimate goal of providing life-changing treatments to large numbers of patients at reduced costs within the point-of-care setting. Specifically, we are focusing on immuno-oncology, metabolic and autoimmune diseases, as well as anti-viral therapies. Most recently, we completed the acquisition of Tamir Biotechnology, Inc., including ranpirnase, a broad spectrum anti-viral platform. Ranpirnase has demonstrated clinical efficacy against HPV and other hard to target viruses based on its unique mechanism of action of killing the virus and modulating the immune system. Having demonstrated clinical activity against human papillomavirus, as well as preclinical activity against some of the worlds most persistent viral threats, we plan to aggressively pursue a number of complementary approaches with a goal to maximize the potential of ranpirnase.

We have received approval from regulators to continue working in our research and development labs during the current COVID-19 pandemic, and we are leveraging all our knowledge and expertise in the field of cell and gene therapy, including anti-viral technologies, in an attempt to find potential COVID-19 cures and therapies. Importantly, we have a strong balance sheet and are strategically positioned to bring a variety of therapies to market in a cost-effective, high-quality and scalable manner.

We also announced a joint venture agreement with RevaTis S.A. to advance the development of autologous therapies utilizing and banking muscle-derived mesenchymal stem cells (mdMSC) as a source of exosomes and other cellular products. Our plan is to combine RevaTis patented technique to obtain mdMSCs through a minimally invasive muscle micro-biopsy with our own automated/closed-systems, 3D printing, and bioreactor technologies. The goal of this JV is to lower the costs and accelerate the timeline of bringing these innovative therapies through the clinic and into commercialization.

The Companys complete financial results are available in the Companys Form 10-Q filed with the Securities and Exchange Commission on May 8, 2020 which is available at http://www.sec.gov and on the Companys website.

About Orgenesis

Orgenesis is a pioneering global biotech company which is unlocking the full potential of personalized therapies and closed processing systems through its Cell & Gene Therapy Biotech Platform, with the ultimate aim of providing life changing treatments at the Point of Care to large numbers of patients at low cost. The Platform consists of: (a) POCare Therapeutics, a pipeline of licensed cell and gene therapies (CGTs), and proprietary scientific knowhow; (b) POCare Technologies, a suite of proprietary and in-licensed technologies which are engineered to create customized processing systems for affordable point of care therapies; and (c) POCare Network, a collaborative, international ecosystem of leading research institutes and hospitals committed to clinical development and supply of CGTs at the point of care. By combining science, technologies and a collaborative network, Orgenesis is able to identify the most promising new therapies and provide a pathway for them to reach patients more quickly, more efficiently and at scale, thereby unlocking the power of cell and gene therapy for all. Additional information is available at: http://www.orgenesis.com.

Notice Regarding Forward-Looking Statements

This press release contains forward-looking statements which are made pursuant to the safe harbor provisions of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities and Exchange Act of 1934, as amended. These forward-looking statements involve substantial uncertainties and risks and are based upon our current expectations, estimates and projections and reflect our beliefs and assumptions based upon information available to us at the date of this release. We caution readers that forward-looking statements are predictions based on our current expectations about future events. These forward-looking statements are not guarantees of future performance and are subject to risks, uncertainties and assumptions that are difficult to predict. Our actual results, performance or achievements could differ materially from those expressed or implied by the forward-looking statements as a result of a number of factors, including, but not limited to, the risk that the acquisition of Tamirs assets will not be successfully integrated with our technologies or that the potential benefits of the acquisition will not be realized, our ability to further develop ranpirnase following the acquisition, our reliance on, and our ability to grow, our point-of-care cell therapy platform, our ability to effectively use the net proceeds from the sale of Masthercell, our ability to achieve and maintain overall profitability, the development of our POCare strategy, the sufficiency of working capital to realize our business plans, the development of our trans-differentiation technology as therapeutic treatment for diabetes which could, if successful, be a cure for Type 1 Diabetes; our technology not functioning as expected; our ability to retain key employees; our ability to satisfy the rigorous regulatory requirements for new procedures; our competitors developing better or cheaper alternatives to our products and the risks and uncertainties discussed under the heading "RISK FACTORS" in Item 1A of our Annual Report on Form 10-K for the fiscal year ended December 31 2019, and in our other filings with the Securities and Exchange Commission. We undertake no obligation to revise or update any forward-looking statement for any reason.

Contact for Orgenesis:David WaldmanCrescendo Communications, LLCTel: 212-671-1021ORGS@crescendo-ir.com

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Orgenesis First Quarter 2020 Revenue Increases 348% to $1.9 Million Reflecting Success of CGT Biotech Platform - GlobeNewswire

Abstract

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Follistatin (FST), a protein that binds myostatin and activin, may have the potential to enhance muscle formation while inhibiting inflammation. Here, we hypothesized that adeno-associated virus 9 (AAV9) delivery of FST enhances muscle formation and mitigates metabolic inflammation and knee OA caused by a high-fat diet in mice. AAV-mediated FST delivery exhibited decreased obesity-induced inflammatory adipokines and cytokines systemically and in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. Together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.

Osteoarthritis (OA) is a multifactorial family of diseases, characterized by cartilage degeneration, joint inflammation, and bone remodeling. Despite the broad impact of this condition, there are currently no disease-modifying drugs available for OA. Previous studies demonstrate that obesity and dietary fatty acids (FAs) play a critical role in the development of OA, and metabolic dysfunction secondary to obesity is likely to be a primary risk factor for OA (1), particularly following joint injury (2, 3). Furthermore, both obesity and OA are associated with a rapid loss of muscle integrity and strength (4), which may contribute directly and indirectly to the onset and progression of OA (5). However, the mechanisms linking obesity, muscle, and OA are not fully understood and appear to involve interactions among biomechanical, inflammatory, and metabolic factors (6). Therefore, strategies that focus on protecting muscle and mitigating metabolic inflammation may provide an attractive target for OA therapies in this context.

A few potential interventions, such as weight loss and exercise, have been proposed to reverse the metabolic dysfunction associated with obesity by improving the quantity or quality of skeletal muscle (7). Skeletal muscle mass is modulated by myostatin, a member of the transforming growth factor (TGF-) superfamily and a potent negative regulator of muscle growth (8), and myostatin is up-regulated in obesity and down-regulated by exercise (9). While exercise and weight loss are the first line of therapy for obesity and OA, several studies have shown difficulty in achieving long-term maintenance of weight loss or strength gain, particularly in frail or aging populations (10). Thus, targeted pharmacologic or genetic inhibition of muscle-regulatory molecules such as myostatin provides a promising approach to improving muscle metabolic health by increasing glucose tolerance and enhancing muscle mass in rodents and humans (8).

Follistatin (FST), a myostatin- and activin-binding protein, has been used as a therapy for several degenerative muscle diseases (11, 12), and loss of FST is associated with reduced muscle mass and prenatal death (13). In the context of OA, we hypothesize that FST delivery using a gene therapy approach has multifactorial therapeutic potential through its influence on muscle growth via inhibition of myostatin activity (14) as well as other members of the TGF- family. Moreover, FST has been reported to reduce the infiltration of inflammatory cells in the synovial membrane (15) and affect bone development (16), and pretreatment with FST has been shown to reduce the severity of carrageenan-induced arthritis (15). However, the potential for FST as an OA therapy has not been investigated, especially in exacerbating pathological conditions such as obesity. We hypothesized that overexpression of FST using a gene therapy approach will increase muscle mass and mitigate obesity-associated metabolic inflammation, as well as the progression of OA, in high-fat diet (HFD)induced obese mice. Mice fed an HFD were treated with a single dose of adeno-associated virus 9 (AAV9) to deliver FST or a green fluorescent protein (GFP) control, and the effects on systemic metabolic inflammation and post-traumatic OA were studied (fig. S1).

Dual-energy x-ray absorptiometry (DXA) imaging of mice at 26 weeks of age (Fig. 1A) showed significant effects of FST treatment on body composition. Control-diet, FST-treated mice (i.e., Control-FST mice) exhibited significantly lower body fat percentages, but were significantly heavier than mice treated with a GFP control vector (Control-GFP mice) (Fig. 1B), indicating that increased muscle mass rather than fat was developed with FST. With an HFD, control mice (HFD-GFP mice) showed significant increases in weight and body fat percentage that were ameliorated by FST overexpression (HFD-FST mice).

(A) DXA images of mice at 26 weeks of age. (B) DXA measurements of body fat percentage and bone mineral density (BMD; 26 weeks) and body weight measurements over time. (C) Serum levels for adipokines (insulin, leptin, resistin, and C-peptide) at 28 weeks. (D) Metabolite levels for glucose, triglycerides, cholesterol, and FFAs at 28 weeks. (E) Serum levels for cytokines (IL-1, IL-1, MCP-1, and VEGF) at 28 weeks. (F) Fluorescence microscopy images of visceral adipose tissue with CD11b:Alexa Fluor 488 (green), CD11c:phycoerythrin (PE) (red), and 4,6-diamidino-2-phenylindole (DAPI; blue). Scale bars, 100 m. Data are presented as mean SEM; n = 8 to 10; two-way analysis of variance (ANOVA), P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis. For IL-1 and VEGF, P < 0.05 for diet effect and AAV effect. For MCP-1, P < 0.05 for diet effect.

In the HFD group, overexpression of FST significantly decreased serum levels of several adipokines including insulin, leptin, resistin, and C-peptide as compared to GFP-treated mice (Fig. 1C). HFD-FST mice also had significantly lower serum levels of glucose, triglycerides, cholesterol, and free FAs (FFAs) (Fig. 1D), as well as the inflammatory cytokine interleukin-1 (IL-1) (Fig. 1E) when compared to HFD-GFP mice. For both dietary groups, AAV-FST delivery significantly increased circulating levels of vascular endothelial growth factor (VEGF) while significantly decreasing IL-1 levels. Furthermore, obesity-induced inflammation in adipose tissue was verified by the presence of CD11b+CD11c+ M1 pro-inflammatory macrophages or dendritic cells (Fig. 1F).

To determine whether FST gene therapy can mitigate injury-induced OA, mice underwent surgery for destabilization of the medial meniscus (DMM) and were sacrificed 12 weeks after surgery. Cartilage degeneration was significantly reduced in DMM joints of the mice receiving FST gene therapy in both dietary groups (Fig. 2, A and C) when compared to GFP controls. FST overexpression also significantly decreased joint synovitis (Fig. 2, B and D) when compared to GFP controls. To evaluate the local influence of pro-inflammatory cytokines to joint degeneration and inflammation, synovial fluid (SF) was harvested from surgical and ipsilateral nonsurgical limbs and analyzed using a multiplexed array. The DMM joints from mice with FST overexpression exhibited a trend toward lower levels of pro-inflammatory cytokines, including IL-1, IL-1, and IL-6, and a higher level of interferon- (IFN-)induced protein (IP-10) in the SF of DMM joints as compared to contralateral controls (Fig. 2E).

(A) Histologic analysis of OA severity via Safranin O (glycosaminoglycans) and fast green (bone and tendon) staining of DMM-operated joints. (B) Histology [hematoxylin and eosin (H&E) staining] of the medial femoral condyle of DMM-operated joints. Thickened synovium (S) from HFD mice with a high density of infiltrated cells was observed (arrows). (C) Modified Mankin scores compared within the diet. (D) Synovitis scores compared within the diet. (E) Levels of proinflammatory cytokines in the SF compared within the diet. (F) Hot plate latency time and sensitivity to cold plate exposure, as measured using the number of jumps in 30 s, both for non-operated algometry measurements of pain sensitivity compared within the diet. Data are presented as mean SEM; n = 5 to 10 mice per group; two-way ANOVA, P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis.

To investigate the effect of FST on pain sensitivity in OA, animals were subjected to a variety of pain measurements including hot plate, cold plate, and algometry. Obesity increased heat withdrawal latency, which was rescued by FST overexpression (Fig. 2F). Cold sensitivity trended lower with obesity, and because no significant differences in heat withdrawal latency were found with surgery (fig. S2), no cold sensitivity was measured after surgery. We found that FST treatment protected HFD animals from mechanical algesia at the knee receiving DMM surgery, while Control-diet DMM groups demonstrated increased pain sensitivity following joint injury.

A bilinear regression model was used to elucidate the relationship among OA severity, biomechanical factors, and metabolic factors (table S1). Factors significantly correlated with OA were then selected for multivariate regression (Table 1). Both multivariate regression models revealed serum tumor necrosis factor- (TNF-) levels as a major predictor of OA severity.

, standardized coefficient. ***P < 0.001.

We analyzed the effects of FST treatment on muscle structure and mass, and performance measures were conducted on mice in both dietary groups. Both Control-FST and HFD-FST limbs exhibited visibly larger muscles compared to both AAV-GFP groups (Fig. 3A). In addition, the muscle masses of tibialis anterior (TA), gastrocnemius, and quadriceps increased significantly with FST treatment (Fig. 3B). Western blot analysis confirmed an increase in FST expression in the muscle at the protein level in FST-treated groups compared to GFP-treated animals in Control and HFD groups (Fig. 3C). Immunofluorescence labeling showed increased expression of FST in muscle (Fig. 3D) and adipose tissue (Fig. 3E) of the AAV-FST mice, with little or no expression of FST in control groups.

(A) Photographic images and (B) measured mass of tibialis anterior (TA), gastrocnemius (GAS), and quadriceps (QUAD) muscles; n = 8, diet and AAV effects both P < 0.05. (C) Western blot showing positive bands of FST protein only in FST-treated muscles, with -actin as a loading control. Immunolabeling of (D) GAS muscle and (E) adipose tissue showing increased expression of FST, particularly in skeletal muscle. (F) H&E-stained sections of GAS muscles were measured for (G) mean myofiber diameter; n = 100 from four mice per group, diet, and AAV effects; both P < 0.05. (H) Oil Red O staining was analyzed for (I) optical density values of FAs; n = 6. (J) Second-harmonic generation imaging of collagen in TA sections was quantified for intensity; n = 6. (K) Western blotting showing the level of phosphorylation markers of protein synthesis in GAS muscle. (L) Functional analysis of grip strength and treadmill time to exhaustion; n = 10. Data are presented as mean SEM; two-way ANOVA, P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis. Photo credit: Ruhang Tang, Washington University.

To determine whether the increases in muscle mass reflected muscle hypertrophy, gastrocnemius muscle fiber diameter was measured in H&E-stained sections (Fig. 3F) at 28 weeks of age. Mice with FST overexpression exhibited increased fiber diameter (i.e., increased muscle hypertrophy) relative to the GFP-expressing mice in both diet treatments (Fig. 3G). Oil Red O staining was used to determine the accumulation of neutral lipids in muscle (Fig. 3H). We found that HFD-FST mice were protected from lipid accumulation in muscles compared to HFD-GFP mice (Fig. 3I). Second-harmonic generation imaging confirmed the presence of increased collagen content in the muscles of HFD mice, which was prevented by FST gene therapy (Fig. 3J). We also examined the expression and phosphorylation levels of the key proteins responsible for insulin signaling in muscles. We observed increased phosphorylation of AktS473, S6KT389, and S6RP-S235/2369 and higher expression of peroxisome proliferatoractivated receptor coactivator 1- (Pgc1-) in muscles from FST mice compared to GFP mice, regardless of diet (Fig. 3K). In addition to the improvements in muscle structure with HFD, FST-overexpressing mice also showed improved function, including higher grip strength and increased treadmill running endurance (Fig. 3L), compared to GFP mice.

Because FST has the potential to influence cardiac muscle and skeletal muscle, we performed a detailed evaluation on the effect of FST overexpression on cardiac function. Echocardiography and short-axis images were collected to visualize the left ventricle (LV) movement during diastole and systole (fig. S3A). While the Control-FST mice had comparable LV mass (LVM) and left ventricular posterior wall dimensions (LVPWD) with Control-GFP mice (fig. S3, B and C), the HFD-FST mice have significantly decreased LVM and trend toward decreased LVPWD compared to HFD-GFP. Regardless of the diet treatments, FST overexpression enhanced the rate of heart weight/body weight (fig. S3D). Although Control-FST mice had slightly increased dimensions of the interventricular septum at diastole (IVSd) compared to Control-GFP (fig. S3E), there was significantly lower IVSd in HFD-FST compared to HFD-GFP. In addition, we found no difference in fractional shortening among all groups (fig. S3F). Last, transmitral blood flow was investigated using pulse Doppler. While there was no difference in iso-volumetric relaxation time (IVRT) in Control groups, HFD-FST mice had a moderate decrease in IVRT compared to HFD-GFP (fig. S3G). Overall, FST treatment mitigated the changes in diastolic dysfunction and improved the cardiac relaxation caused by HFD.

DXA demonstrated that FST gene therapy improved bone mineral density (BMD) in HFD compared to other groups (Fig. 1B). To determine the effects of injury, diet intervention, and overexpression of FST on bone morphology, knee joints were evaluated by microcomputed tomography (microCT) (Fig. 4A). The presence of heterotopic ossification was observed throughout the GFP knee joints, whereas FST groups demonstrated a reduction or an absence of heterotopic ossification. FST overexpression significantly increased the ratio of bone volume to total volume (BV/TV), BMD, and trabecular number (Tb.N) of the tibial plateau in animals, regardless of diet treatment (Fig. 4B). Joint injury generally decreased bone parameters in the tibial plateau, particularly in Control-diet mice. In the femoral condyle, BV/TV and Tb.N were significantly increased in mice with FST overexpression in both diet types, while BMD was significantly higher in HFD-FST compared to HFD-GFP mice (Fig. 4B). Furthermore, AAV-FST delivery significantly increased trabecular thickness (Tb.Th) and decreased trabecular space (Tb.Sp) in the femoral condyle of HFD-FST compared to HFD-GFP animals (fig. S4).

(A) Three-dimensional (3D) reconstruction of microCT images of non-operated and DMM-operated knees. (B) Tibial plateau (TP) and femoral condyle (FC) regional analyses of trabecular bone fraction bone volume (BV/TV), BMD, and trabecular number (Tb.N). Data are presented as mean SEM; n = 8 to 19 mice per group; two-way ANOVA. (C) 3D microCT reconstruction of metaphysis region of DMM-operated joints. (D) Analysis of metaphysis BV/TV, Tb.N, and BMD. (E) 3D microCT reconstruction of cortical region of DMM-operated joints. (F) Analysis of cortical cross-sectional thickness (Ct.Cs.Th), polar moment of inertia (MMI), and tissue mineral density (TMD). (D and F) Data are presented as mean SEM; n = 8 to 19 mice per group; Mann-Whitney U test, *P < 0.05.

Further microCT analysis was conducted on the trabecular (Fig. 4C) and cortical (Fig. 4E) areas of the metaphyses. FST gene therapy significantly increased BV/TV, Tb.N, and BMD in the metaphyses regardless of the diet (Fig. 4D). Furthermore, FST delivery significantly increased the cortical cross-sectional thickness (Ct.Cs.Th) and polar moment of inertia (MMI) of mice on both diet types, as well as tissue mineral density (TMD) of cortical bones of mice fed control diet (Fig. 4F).

To elucidate the possible mechanisms by which FST mitigates inflammation, we examined the browning/beiging process in subcutaneous adipose tissue (SAT) with immunohistochemistry (Fig. 5A). Here, we found that key proteins expressed mainly in brown adipose tissue (BAT) (PGC-1, PRDM16, thermogenesis marker UCP-1, and beige adipocyte marker CD137) were up-regulated in SAT of the mice with FST overexpression (Fig. 5B). Increasing evidence suggests that an impaired mitochondrial oxidative phosphorylation (OXPHOS) system in white adipocytes is a hallmark of obesity-associated inflammation (17). Therefore, we further examined the mitochondrial respiratory system in SAT. HFD reduced the amount of OXPHOS complex subunits (Fig. 5C). We found that proteins involved in OXPHOS, including subunits of complexes I, II, and III of mitochondria OXPHOS complex, were significantly up-regulated in AAV-FSToverexpressing animals compared to AAV-GFP mice (Fig. 5D).

(A) Immunohistochemistry of UCP-1 expression in SAT. Scale bar, 50 m. (B) Western blotting of SAT for key proteins expressed in BAT, with -actin as a loading control. (C) Western blot analysis of mitochondria lysates from SAT for OXPHOS proteins using antibodies against subunits of complexes I, II, III, and IV and adenosine triphosphate (ATP) synthase. (D) Change of densitometry quantification normalized to the average FST level of each OXPHOS subunit. Data are presented as mean SEM; n = 3. *P < 0.05, t test comparison within each pair.

Our findings demonstrate that a single injection of AAV-mediated FST gene therapy ameliorated systemic metabolic dysfunction and mitigated OA-associated cartilage degeneration, synovial inflammation, and bone remodeling occurring with joint injury and an HFD. Of note, the beneficial effects were observed across multiple tissues of the joint organ system, underscoring the value of this potential treatment strategy. The mechanisms by which obesity and an HFD increase OA severity are complex and multifactorial, involving increased systemic metabolic inflammation, joint instability and loss of muscle strength, and synergistic interactions between local and systemic cytokines (4, 6). In this regard, the therapeutic consequences of FST gene therapy also appear to be multifactorial, involving both direct and indirect effects such as increased muscle mass and metabolic activity to counter caloric intake and metabolic dysfunction resulting from an HFD while also promoting adipose tissue browning. Furthermore, FST may also serve as a direct inhibitor of growth factors in the TGF- family that may be involved in joint degeneration (18).

FST gene therapy showed a myriad of notable beneficial effects on joint degeneration following joint injury while mitigating HFD-induced obesity. These data also indirectly implicate the critical role of muscle integrity in the onset and progression of post-traumatic OA in this model. It is important to note that FST gene therapy mitigated many of the key negative phenotypic changes previously associated with obesity and OA, including cartilage structural changes as well as bone remodeling, synovitis, muscle fibrosis, and increased pain, as compared to GFP controls. To minimize the number of animals used, we did not perform additional controls with no AAV delivery; however, our GFP controls showed similar OA changes as observed in our previous studies, which did not involve any gene delivery (2). Mechanistically, FST restored to control levels a number of OA-associated cytokines and adipokines in the serum and the SF. While the direct effects of FST on chondrocytes remains to be determined, FST has been shown to serve as a regulator of the endochondral ossification process during development (19), which may also play a role in OA (20). Furthermore, previous studies have shown that a 2-week FST treatment of mouse joints is beneficial in reducing infiltration of inflammatory cells into the synovial membrane (15). Our findings suggest that FST delivery in skeletally mature mice, preceding obesity-induced OA changes, substantially reduces the probability of tissue damage.

It is well recognized that FST can inhibit the activity of myostatin and activin, both of which are up-regulated in obesity-related modalities and are involved in muscle atrophy, tissue fibrosis, and inflammation (21). Consistent with previous studies, our results show that FST antagonizes the negative regulation of myostatin in muscle growth, reducing adipose tissue content in animals. Our observation that FST overexpression decreased inflammation at both serum systemic and local joint inflammation may provide mechanistic insights into our findings of mitigated OA severity in HFD-fed mice. Our statistical analysis implicated serum TNF- levels as a major factor in OA severity, consistent with previous studies linking obesity and OA in mice (22). Although the precise molecular mechanisms of FST in modulating inflammation remain unclear, some studies postulate that FST may act like acute-phase protein in lipopolysaccharide-induced inflammation (23).

In addition to these effects of skeletal muscle, we found that FST gene therapy normalized many of the deleterious changes of an HFD on cardiac function without causing hypertrophy. These findings are consistent with previous studies showing that, during the process of aging, mice with myostatin knockout had an enhanced cardiac stress response (24). Furthermore, FST has been shown to regulate activin-induced cardiomyocyte apoptosis (1). In the context of this study, it is also important to note that OA has been shown to be a serious risk factor for progression of cardiovascular disease (25), and severity of OA disability is associated with significant increases in all-cause mortality and cardiovascular events (26).

FST gene therapy also rescued diet- and injury-induced bone remodeling in the femoral condyle, as well as the tibial plateau, metaphysis, and cortical bone of the tibia, suggesting a protective effect of FST on bone homeostasis of mice receiving an HFD. FST is a known inhibitor of bone morphogenetic proteins (BMPs), and thus, the interaction between the two proteins plays an essential role during bone development and remodeling. For example, mice grown with FST overexpression via global knock-in exhibited an impaired bone structure (27). However, in adult diabetic mice, FST was shown to accelerate bone regeneration by inhibiting myostatin-induced osteoclastogenesis (28). Furthermore, it has been reported that FST down-regulates BMP2-driven osteoclast activation (29). Therefore, the protective role of FST on obesity-associated bone remodeling, at least in part, may result from the neutralizing capacity of FST on myostatin in obesity. In addition, improvement in bone quality in FST mice may be explained by their enhanced muscle mass and strength, as muscle mass can dominate the process of skeletal adaptation, and conversely, muscle loss correlates with reduced bone quality (30).

Our results show that FST delivery mitigated pain sensitivity in OA joints, a critical aspect of clinical OA. Obesity and OA are associated with both chronic pain and pain sensitization (31), but it is important to note that structure and pain can be uncoupled in OA (32), necessitating the measurement of both behavioral and structural outcomes. Of note, FST treatment protected only HFD animals from mechanical algesia at the knee post-DMM surgery and also rescued animals from pain sensitization induced by HFD in both the DMM and nonsurgical limb. The mitigation in pain sensitivity observed here with FST treatment may also be partially attributed to the antagonistic effect of FST on activin signaling. In addition to its role in promoting tissue fibrosis, activin A has been shown to regulate nociception in a manner dependent on the route of injection (33, 34). It has been shown that activin can sensitize the transient receptor potential vanilloid 1 (TRPV1) channel, leading to acute thermal hyperalgesia (33). However, it is also possible that activin may induce pain indirectly, for example, by triggering neuroinflammation (35), which could lead to sensitization of nociceptors.

The earliest detectable abnormalities in subjects at risk for developing obesity and type 2 diabetes are muscle loss and accumulation of excess lipids in skeletal muscles (4, 36), accompanied by impairments in nuclear-encoded mitochondrial gene expression and OXPHOS capacity of muscle and adipose tissues (17). PGC-1 activates mitochondrial biogenesis and increases OXPHOS by increasing the expression of the transcription factors necessary for mitochondrial DNA replication (37). We demonstrated that FST delivery can rescue low levels of OXPHOS in HFD mice by increasing expression PGC-1 (Fig. 3H). It has been reported that high-fat feeding results in decreased PGC-1 and mitochondrial gene expression in skeletal muscles, while exercise increases the expression of PGC-1 in both human and rodent muscles (38, 39). Although the precise molecular mechanism by which FST promotes PGC-1 expression has not been established, the infusion of lipids decreases expression of PGC-1 and nuclear-encoded mitochondrial genes in muscles (40). Thus, decreased lipid accumulation in muscle by FST overexpression may provide a plausible explanation for the restored PGC-1 in the FST mice. These findings were further confirmed by the metabolic profile, showing reduced serum levels of triglycerides, glucose, FFAs, and cholesterol (Fig. 1D), and are consistent with previous studies, demonstrating that muscles with high numbers of mitochondria and oxidative capacity (i.e., type 1 muscles with high levels of PGC-1 expression) are protected from damage due to an HFD (4).

In addition, we found increased phosphorylation of protein kinase B (Akt) on Ser473 in the skeletal muscle of FST-treated mice as compared to untreated HFD counterparts (Fig. 3K), consistent with restoration of a normal insulin response. A number of studies have demonstrated that the serine-threonine protein kinase Akt1 is a critical regulator of cellular hypertrophy, organ size, and insulin signaling (41). Muscle hypertrophy is stimulated both in vitro and in vivo by the expression of constitutively active Akt1 (42, 43). Furthermore, it has been demonstrated that constitutively active Akt1 also promotes the production of VEGF (44).

BAT is thought to be involved in thermogenesis rather than energy storage. BAT is characterized by a number of small multilocular adipocytes containing a large number of mitochondria. The process in which white adipose tissue (WAT) becomes BAT, called beiging or browning, is postulated to be protective in obesity-related inflammation, as an increase in BAT content positively correlates with increased triglyceride clearance, normalized glucose level, and reduced inflammation. Our study shows that AAV-mediated FST delivery serves as a very promising approach to induce beiging of WAT in obesity. A recent study demonstrated that transgenic mice overexpressing FST exhibited an increasing amount of BAT and beiging in subcutaneous WAT with increased expression of key BAT-related markers including UCP-1 and PRDM16 (45). In agreement with previous reports, our data show that Ucp1, Prdm16, Pgc1a, and Cd167 are significantly up-regulated in SAT of mice overexpressing FST in both dietary interventions. FST has been recently demonstrated to play a crucial role in modulating obesity-induced WAT expansion by inhibiting TGF-/myostatin signaling and thus promoting overexpression of these key thermogenesis-related genes. Together, these findings suggest that the observed reduction in systemic inflammation in our model may be partially explained by FST-mediated increased process of browning/beiging.

In conclusion, we show that a single injection of AAV-mediated FST, administered after several weeks of HFD feeding, mitigated the severity of OA following joint injury, and improved muscle performance as well as induced beiging of WAT, which together appeared to decrease obesity-associated metabolic inflammation. These findings provide a controlled model for further examining the differential contributions of biomechanical and metabolic factors to the progression of OA with obesity or HFD. As AAV gene therapy shows an excellent safety profile and is currently in clinical trials for a number of conditions, such an approach may allow the development of therapeutic strategies not only for OA but also, more broadly, for obesity and associated metabolic conditions, including diseases of muscle wasting.

All experimental procedures were approved by and conducted in accordance with the Institutional Animal Care and Use Committee guidelines of Washington University in Saint Louis. The overall timeline of the study is shown in fig. S1A. Beginning at 5 weeks of age, C57BL/6J mice (The Jackson Laboratory) were fed either Control or 60% HFD (Research Diets, D12492). At 9 week of age, mice received AAV9-mediated FST or GFP gene delivery via tail vein injection. A total of 64 mice with 16 mice per dietary group per AAV group were used. DMM was used to induce knee OA in the left hind limbs of the mice at the age of 16 weeks. The non-operated right knees were used as contralateral controls. Several behavioral activities were measured during the course of the study. Mice were sacrificed at 28 weeks of age to evaluate OA severity, joint inflammation, and joint bone remodeling.

Mice were weighed biweekly. The body fat content and BMD of the mice were measured using a DXA (Lunar PIXImus) at 14 and 26 weeks of age, respectively.

Complementary DNA synthesis for mouse FST was performed by reverse transcriptase in a reverse transcription quantitative polymerase chain reaction (RT-qPCR) ( Invitrogen) mixed with mRNAs isolated from the ovary tissues of C57BL/6J mouse. The PCR product was cloned into the AAV9-vector plasmid (pTR-UF-12.1) under the transcriptional control of the chicken -actin (CAG) promoter including cytomegalovirus (CMV) enhancers and a large synthetic intron (fig. S1B). Recombinant viral vector stocks were produced at Hope Center Viral Vectors Core (Washington University, St. Louis) according to the plasmid cotransfection method and suspension culture. Viral particles were purified and concentrated. The purity of AAV-FST and AAV-GFP was evaluated by SDSpolyacrylamide gel electrophoresis (PAGE) and stained by Coomassie blue. The results showed that the AAV protein components in 5 1011 vector genomes (vg) are only stained in three major protein bands: VR1, 82 kDa; VR2, 72 kDa; and VR3, 62 kDa. Vector titers were determined by the DNA dot-blot and PCR methods and were in the range of 5 1012 to 1.5 1013 vector copies/ml. AAV was delivered at a final dose of 5 1011 vg per mouse by intravenous tail injection under red light illumination at 9 weeks of age. This dose was determined on the basis of our previous studies showing that AAV9-FST gene delivery by this route resulted in a doubling of muscle mass at a dose of 2.5 1011 vg in 4-week-old mice or at 5 1011 vg in 8-week-old mice (46).

At 16 weeks of age, mice underwent surgery for the DMM to induce knee OA in the left hindlimb as previously described (2). Briefly, anesthetized mice were placed on a custom-designed device, which positioned their hindlimbs in 90 flexion. The medial side of the joint capsule was opened, and the medial meniscotibial ligament was transected. The joint capsule and subcutaneous layer of the skin were closed with resorbable sutures.

Mice were sacrificed at 28 weeks of age, and changes in joint structure and morphology were assessed using histology. Both hindlimbs were harvested and fixed in 10% neutral-buffered formalin (NBF). Limbs were then decalcified in Cal-Ex solution (Fisher Scientific, Pittsburgh, PA, USA), dehydrated, and embedded in paraffin. The joint was sectioned in the coronal plane at a thickness of 8 m. Joint sections were stained with hematoxylin, fast green, and Safranin O to determine OA severity. Three blinded graders then assessed sections for degenerative changes of the joint using a modified Mankin scoring system (2). Briefly, this scoring system measures several aspects of OA progression (cartilage structure, cell distribution, integrity of tidemark, and subchondral bone) in four joint compartments (medial tibial plateau, medial femoral condyle, lateral tibial plateau, and lateral femoral condyle), which are summed to provide a semiquantitative measure of the severity of joint damage. To assess the extent of synovitis, sections were stained with H&E to analyze infiltrated cells and synovial structure. Three independent blinded graders scored joint sections for synovitis by evaluating synovial cell hyperplasia, thickness of synovial membrane, and inflammation in subsynovial regions in four joint compartments, which were summed to provide a semiquantitative measure of the severity of joint synovitis (2). Scores for the whole joint were averaged among graders.

Serum and SF from the DMM and contralateral control limbs were collected, as described previously (2). For cytokine and adipokine levels in the serum and SF fluid, a multiplexed bead assay (Discovery Luminex 31-Plex, Eve Technologies, Calgary, AB, Canada) was used to determine the concentration of Eotaxin, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), IFN-, IL-1, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A, IP-10, keratinocyte chemoattractant (KC), leukemia inhibitory factor (LIF), liposaccharide-induced (LIX), monocyte chemoattractant protein-1 (MCP-1), M-CSF, monokine induced by gamma interferon (MIG), macrophage inflammatory protein1 (MIP-1), MIP-1, MIP-2, RANTES, TNF-, and VEGF. A different kit (Mouse Metabolic Array) was used to measure levels for amylin, C-peptide, insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), ghrelin, glucagon, insulin, leptin, protein phosphatase (PP), peptide yy (PYY), and resistin. Missing values were imputed using the lowest detectable value for each analyte.

Muscles were cryopreserved by incubation with 2-methylbutane in a steel beaker using liquid nitrogen for 30 s, cryoembedded, and cryosectioned at 8 m thickness. Tissue sections were stained following standard H&E protocol. Photomicrographs of skeletal muscle fiber were imaged under brightfield (VS120, Olympus). Muscle slides fixed in 3.7% formaldehyde were stained with 0.3% Oil Red O (in 36% triethyl phosphate) for 30 min. Images were taken in brightfield (VS120, Olympus). The relative concentration of lipid was determined by extracting the Oil Red O with isopropanol in equally sized muscle sections and quantifying the OD500 (optical density at 500 nm) in a 96-well plate.

To determine spatial expression of FST in different tissues, cryosections of gastrocnemius muscles and adipose tissue were immunolabeled for FST. Tissue sections were fixed in 1.5% paraformaldehyde solution, and primary anti-FST antibody (R&D Systems, AF-669, 1:50) was incubated overnight at 4C after blocking with 2.5% horse serum (Vector Laboratories), followed by labeling with a secondary antibody (Alexa Fluor 488, Invitrogen, A11055) and with 4,6-diamidino-2-phenylindole (DAPI) for cell nuclei. Sections were imaged using fluorescence microscopy.

Second-harmonic generation images of TA were obtained from unstained slices using backscatter signal from an LSM 880 confocal microscope (Zeiss) with Ti:sapphire laser tuned to 820 nm (Coherent). The resulting image intensity was analyzed using ImageJ software.

To measure bone structural and morphological changes, intact hindlimbs were scanned by microCT (SkyScan 1176, Bruker) with an 18-m isotropic voxel resolution (455 A, 700-ms integration time, and four-frame averaging). A 0.5-mm aluminum filter was used to reduce the effects of beam hardening. Images were reconstructed using NRecon software (with 10% beam hardening and 20 ring artifact corrections). Subchondral/trabecular and cortical bone regions were segmented using CTAn automatic thresholding software. Tibial epiphysis was selected using the subchondral plate and growth plate as references. Tibial metaphysis was defined as the 1-mm region directly below the growth plate. The cortical bone analysis was performed in the mid-shaft (4 mm below the growth plate with a height of 1 mm). Hydroxyapatite calibration phantoms were used to calibrate bone density values (mg/cm3).

Fresh visceral adipose tissues were collected, frozen in optimal cutting temperature compound (OCT), and cryosectioned at 5-m thickness. Tissue slides were then acetone-fixed followed by incubation with Fc receptor blocking in 2.5% goat serum (Vector Laboratories) and incubation with primary antibodies cocktail containing anti-CD11b:Alexa Fluor 488 and CD11c:phycoerythrin (PE) (BioLegend). Nuclei were stained with DAPI. Samples were imaged using fluorescence microscopy (VS120, Olympus).

Adipose tissues were fixed in 10% NBF, paraffin-embedded, and cut into 5-m sections. Sections were deparaffinized, rehydrated, and stained with H&E. Immunohistochemistry was performed by incubating sections (n = 5 per each group) with the primary antibody (antimUCP-1, U6382, Sigma), followed by a secondary antibody conjugated with horseradish peroxidase (HRP). Chromogenic substrate 3,3-diaminobenzidine (DAB) was used to develop color. Counterstaining was performed with Harris hematoxylin. Sections were examined under brightfield (VS120, Olympus).

Proteins of the muscle or fat tissue were extracted using lysis buffer containing 1% Triton X-100, 20 mM tris-HCl (pH 7.5), 150 mM NaCl, 1 mm EDTA, 5 mM NaF, 2.5 mM sodium pyrophosphate, 1 mM -glycerophosphate, 1 mM Na3VO4, leupeptin (1 g ml1), 0.1 mM phenylmethylsulfonyl fluoride, and a cocktail of protease inhibitors (Sigma, St. Louis, MO, USA, catalog no. P0044). Protein concentrations were measured with Quick Start Bradford Dye Reagent (Bio-Rad). Twenty micrograms of each sample was separated in SDS-PAGE gels with prestained molecular weight markers (Bio-Rad). Proteins were wet-transferred to polyvinylidene fluoride membranes. After incubating for 1.5 hours with a buffer containing 5% nonfat milk (Bio-Rad #170-6404) at room temperature in 10 mM tris-HCl (pH 7.5), 100 mM NaCl, and 0.1% Tween 20 (TBST), membranes were further incubated overnight at 4C with antiUCP-1 rabbit polyclonal antibody (1:500, Sigma, U6382), anti-PRDM16 rabbit antibody (Abcam, ab106410), anti-CD137 rabbit polyclonal antibody (1:1000, Abcam, ab203391), total OXPHOS rodent western blot (WB) antibodies (Abcam, ab110413), anti-actin (Cell Signaling Technology, 13E5) rabbit monoclonal antibody (Cell Signaling Technology, 4970), followed by HRP-conjugated secondary antibody incubation for 30 min. A chemiluminescent detection substrate (Clarity, Western ECL) was applied, and the membranes were developed (iBrightCL1000).

The effects of HFD and FST gene therapy on thermal hyperalgesia were examined at 15 weeks of age. Mice were acclimatized to all equipment 1 day before the onset of testing, as well as a minimum of 30 min before conducting each test. Thermal pain tests were measured in a room set to 25C. Peripheral thermal sensitivity was determined using a hot/cold analgesia meter (Harvard Apparatus, Holliston, MA, USA). For hot plate testing, the analgesia meter was set to 55C. To prevent tissue damage, a maximum cutoff time of 20 s was established a priori, at which time an animal would be removed from the plate in the absence of pain response, defined as paw withdrawal or licking. Animals were tested in the same order three times, allowing each animal to have a minimum of 30 min between tests. The analgesia meter was cleaned with 70% ethanol between trials. The average of the three tests was reported per animal. To evaluate tolerance to cold, the analgesia meter was set to 0C. After 1-hour rest, animals were tested for sensitivity to cold over a single 30-s exposure. The number of jumps counted per animal was averaged within each group and compared between groups.

Pressure-pain tests were conducted at the knee using a Small Animal Algometer (SMALGO, Bioseb, Pinellas Park, FL, USA). Surgical and nonsurgical animals were evaluated over serial trials on the lateral aspect of the experimental and contralateral knee joints. The average of three trials per limb was calculated for each limb. Within each group, the pain threshold of the DMM limb versus non-operated limb was compared using a t test run on absolute values of mechanical pain sensitivity for each limb, P 0.05.

To assess the effect of HFD and AAV-FST treatments on neuromuscular function, treadmill running to exhaustion (EXER3, Columbus Instruments) was performed at 15 m/min, with 5 inclination angle on the mice 4 months after gene delivery. Treadmill times were averaged within groups and compared between groups.

Forelimb grip strength was measured using Chatillon DFE Digital Force Gauge (Johnson Scale Co.) for front limb strength of the animals. Each mouse was tested five times, with a resting period of 90 s between each test. Grip strength measurements were averaged within groups and compared between groups.

Cardiac function of the mice was examined at 6 months of age (n = 3) using echocardiography (Vevo 2100 High-Resolution In Vivo Imaging System, VisualSonics). Short-axis images were taken to view the LV movement during diastole and systole. Transmitral blood flow was observed with pulse Doppler. All data and images were performed by a blinded examiner and analyzed with an Advanced Cardiovascular Package Software (VisualSonics).

Detailed statistical analyses are described in methods of each measurement and its corresponding figure captions. Analyses were performed using GraphPad Prism, with significance reported at the 95% confidence level.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Acknowledgments: Funding: This study was supported, in part, by NIH grants AR50245, AR48852, AG15768, AR48182, AG46927, AR073752, OD10707, AR060719, AR074992, and AR75899; the Arthritis Foundation; and the Nancy Taylor Foundation for Chronic Diseases. Author contributions: R.T. and F.G. developed the concept of the study; R.T., N.S.H., C.-L.W., K.H.C., and Y.-R.C. collected and analyzed data; S.J.O. analyzed data; and all authors contributed to the writing of the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

Link:
Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat dietinduced obesity - Science Advances

BOSTON--(BUSINESS WIRE)--Decibel Therapeutics, a clinical-stage biotechnology company developing novel gene therapeutics for restoration of hearing loss and balance disorders, today announced that it will present new findings on its pipeline and platform at the 23rd Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), which will be held virtually from May 1215.

Decibels platform utilizes leading single-cell genomics and bioinformatics capabilities to enable AAV-based gene therapy to restore functionality of cochlear and vestibular hair cells in multiple forms of hearing loss and balance disorders. The company has used its platform to identify a suite of genetic control elements enabling cell-specific expression in each of the key cell types of the inner ear. Decibel is further identifying key reprogramming factors to regenerate hair cells in the inner ear by gene therapy or small molecules.

Decibel will deliver three presentations:

The research our team will share at ASGCT represents the progress we have made in developing our precision AAV platform to deliver genes that can restore hearing and balance function, said John Lee, CSO of Decibel. Our AAV platform, combined with our single-cell genomics and bioinformatics capabilities, is driving our progress to create transformative therapeutics for people who are living with severe hearing loss and balance disorders.

The three presentations the Decibel team will share during the conference are the following:

Dual AAV Delivery of Otoferlin Durably Rescues Hearing in Congenitally Deaf Preclinical ModelsPresenter: Jonathon Whitton, Au.D., Ph.D. Session Title: Gene Therapy for the Special Senses Date & Time: Tuesday, May 12, 11:15 a.m.

Tailored AAV-Based Transgene Expression in the Inner Ear with Cell Type-Specific PromotersPresenter: Adam Palermo, Ph.D. Session Title: Controlling AAV Gene Expression: Shifting Paradigms Date & Time: Wednesday, May 13, 4:45 p.m.

A Transient Burst of Transgene Expression Promotes Regeneration of Mature Vestibular Hair CellsPresenter: Joseph Burns, Ph.D. Session Title: AAV Vectors Preclinical and Proof-of-Concept Studies in CNS Disorders Date & Time: Friday, May 15, 10:45 a.m.

About Decibel Therapeutics, Inc.

Decibel Therapeutics, a clinical-stage biotechnology company, has established the worlds first comprehensive drug discovery, development and translational research platform for hearing loss and balance disorders. Decibel is advancing a portfolio of discovery-stage programs aimed at restoring hearing and balance function to further our vision of a world in which the benefits and joys of hearing are available to all. Decibels lead therapeutic candidate, DB-020, is being investigated for the prevention of ototoxicity associated with cisplatin chemotherapy. For more information about Decibel Therapeutics, please visit decibeltx.com or follow @DecibelTx.

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Decibel Therapeutics to Present at the 23rd Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT) - Business Wire

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Size & Share Of Cell and Gene Therapy Consumables Market 2020 Report Including COVID-19 Impact Analysis And Forecast Till 2026 - Bandera County...

Merck is moving its global headquarters slightly.

After five years at Schering-Ploughs old 100-acre campus in Kenilworth, the company announced plans to transition its base to its 210-acre site in Rahway. The two New Jersey towns are less than 10 miles apart. The move, quietly announced in the companys Q1 and reported on by ROINJ, is slated to be completed by 2023.

The shift will not only mean moving the headquarters but also consolidating the offices scattered across New Jersey, including inMadison, Whitehouse West and Branchburg. No employees are expected to be laid off, the company said.

We announced our intention to consolidate our New Jersey campuses into a single New Jersey location in Rahway, the company said in an emailed statement. Rahway, the birthplace of lifechanging scientific breakthroughs that have improved human health over the last century, will once again be Mercks global headquarters by the end of 2023. We remain committed to New Jersey and invested in the state as the home of our global headquarters.

The move to Rahway is something of a homecoming for Merck. The pharma giant was based in Rahway until 1992, until it moved to Whitehouse Station in Readington, a small town in rural western New Jersey. The company hired a legendary architectural firm to build what became known as the Merck Headquarters Building on woods and old farmland, a jagged hexagon, circumscribed by trees, with trees nestled in the center.

In 2012, Merck said they would shutter the campus and, after a shakeup that saw the closing of the would-be new headquarters in Summit, NJ and the layoff of 8,500 employees worldwide, moved their base to Kenilworth. The Merck Headquarters Building has since been purchased by UNICOM and renamed UNICOM Science and Technology Park.

Although originally established in 1889 in New York City then as the US subsidiary of the German Merck Merck built a manufacturing facility in Rahway in 1902, and, with the addition of research facilities, the site became the headquarters until the 1992 move.

See the article here:
UPDATED: Merck to move global headquarters, returning to an old home - Endpoints News

Image source: The Motley Fool.

Sangamo Therapeutics Inc(NASDAQ:SGMO)Q12020 Earnings CallMay 11, 2020, 5:00 p.m. ET

Operator

Good afternoon, and welcome to the Sangamo Therapeutics Teleconference to discuss First Quarter 2020 Financial Results. This call is being recorded.

I will now pass you over to the coordinator of this event, McDavid Stilwell, Senior Vice President of Corporate Communications and Investor Relations.

McDavid Stilwell -- Senior Vice President of Corporate Communications and Investor Relations

Good afternoon, and thank you for joining us today. With me this afternoon on this call are several members of the Sangamo senior management team, including Sandy Macrae, Chief Executive Officer; Sung Lee, Chief Financial Officer; Stephane Boissel, Head of Corporate Strategy; Adrian Woolfson, Head of Research and Development; Mark McClung, Chief Business Officer; and Bettina Cockroft, Chief Medical Officer.

Slides from our corporate presentation can be found in our website sangamo.com under the Investors and Media section in the Events and Presentations page.

This call includes forward-looking statements regarding Sangamo's current expectations. These statements include, but are not limited to, statements relating to our pipeline of genomic medicine product candidates, our ability to develop, obtain regulatory approval for and commercialize therapies to treat certain diseases and the timing, availability and costs of such therapies, plans and timelines for Sangamo and our collaborators to conduct clinical trials and share clinical data and the potential for these trials to provide clinical benefit to patients, the potential to use certain technologies to develop our therapies, the financial and operational impacts of our collaboration, plans and timelines for building and opening manufacturing facilities, the evolving COVID-19 pandemic and our expectations regarding our financial performance and resources. Actual results may differ substantially from what we discuss today. In addition, these statements are not guarantees of future performance and are subject to certain risks and uncertainties that are discussed in documents that we file with the Securities and Exchange Commission. Specifically in our most recent quarterly report on Form 10-Q filed today and our annual report on Form 10-K. The forward-looking statements stated today are made as of this date and we undertake no duty to update such information, except as required under applicable law.

On this call, we discuss the non-GAAP financial measure. We believe this measure is helpful in understanding our past financial performance and our potential future results. This is not meant to be considered in isolation or as a substitute for the comparable GAAP measure. The comparable GAAP measure and reconciliations of GAAP to the non-GAAP measure discussed on this call are included in today's press release, which is available on our website.

And now, I'd like to turn the call over to Sandy.

Sandy Macrae -- President and Chief Executive Officer

Thank you, McDavid, and good afternoon to everyone on the call. Typically, when I come together with the Sangamo executive team to talk to you about our business every quarter, we are in the boardroom of the headquarters in Brisbane, California. Today, due to the COVID-19 pandemic, we're all in our home offices. One of the many adaptations we've all had to make in these unprecedented circumstances.

At Sangamo, over the last two months, we've worked together to minimize any impact of the pandemic on our business, and I believe that we are in a very strong position. Last month, we were very pleased to announce the closing of our collaboration agreement with Biogen to develop gene regulation therapies for Alzheimer's disease, Parkinson's disease, neuromuscular and other neurological diseases. We have received from Biogen $225 million in proceeds from the sale of stock and an additional $125 million upfront license fee payment. With this $350 million received from Biogen and in addition to the $363 million in cash resources that we reported on our March 31 balance sheet, we believe we have the financial strength to execute on our wholly owned and partnered development programs beyond multiple important milestones, including the potential filing of the BLA for SB-525 for hemophilia A.

In response to COVID-19, Sangamo has prioritized employee safety, and welfare, while responsibly advancing the business. Following the shelter-in-place guidance from government authorities in the middle of March, we asked all non-lab employees to work from home. We also implemented modified labs operations and updated safety protocols to continue critical research and manufacturing work while protecting employee safety and adhering to social distance guidelines. In the labs, we are strategically prioritizing projects to keep our business on track, including focusing on research activities for partnered programs. We are also conducting clinical activities cautiously, so as not to contribute unnecessarily to the current stream in the healthcare system, while seeing close communication with trial sites to protect the safety of the patients in our trial.

We continue to be optimistic that our AAV manufacturing facility in our Brisbane headquarters will be operational by the end of this year. We also expect our cell therapy manufacturing units in Brisbane, California and in Valbonne, France to be opened by the end of 2021. Furthermore, we are keeping in regular contact with our CDMO partners and as of now, do not anticipate any COVID-19-related manufacturing delays with our activities.

Despite the challenges of the current environment, we continue to actively pursue new partnerships both inbound to access new technology, as well as out-licensing deals such as established ones that we already have with Pfizer, Gilead, Sanofi, Biogen and Takeda. An important example of an inbound partnership is our recently announced collaboration and exclusive license with Mogrify, a Cambridge UK company developing novel cell conversion technology that has the potential to serve as a renewable cell source. Under the terms of this agreement, Sangamo aim to use Mogrify's proprietary cell conversion technology to develop allogeneic, zinc finger protein gene-engineered CAR-Treg cell therapies using iPSC-derived regulatory T-cells. This license agreement will diversify our options and complement our current efforts as we develop off-the-shelf allogeneic CAR-Treg cell therapies. We believe that this exciting collaboration has the potential to accelerate the development and manufacturing of novel renewable cell source, Treg therapies.

We are also continuing our discussions on out-licensing opportunities. As a reminder, our strategy for collaborations is to advance select development programs in partnership with biopharmaceutical companies in situations where we believe that our partners' financial resources or clinical and therapeutic area expertise may enable more rapid development and availability of new treatment to patients.

Before I turn the call over to the team, I want to update you on some recent transitions among my direct reports that are natural part of Sangamo's evolution, as we advance our clinical development and strategic partnering. Over the last three years, we've added Executive Vice Presidents to lead manufacturing, legal, finance and R&D. In our latest executive appointment, as we look to the future and perceive the need for commercial development expertise and capabilities, Mark McClung has joined Sangamo as Chief Business Officer and now leads commercial strategic planning, alliance management and corporate and business development. Mark has a distinguished career leading commercial organizations, including GSK, Onyx and Amgen in highly competitive therapeutic areas that require a deep scientific knowledge and where innovative products have disrupted the standards of care and where successful product development occurs as a result in a tightly integrating patient and physician insights into late stage clinical development programs.

Stephane Boissel, our EVP of Corporate Strategy will leave Sangamo at the end of in July and plans to return to an entrepreneurial project. Stephane joined Sangamo in 2018 after we acquired TxCell, now Sangamo France, which Stephane lead as CEO. His energy and vision resulted in our recent Biogen transaction, which is one of the largest pre-clinical collaboration deals ever in the biopharmaceutical industry. Stephane's impactful contribution to Sangamo will endure for many years.

With that, I will turn the call over to our Chief Medical Officer, Bettina.

Bettina Cockroft -- Senior Vice President and Chief Medical Officer

Good afternoon. In light of the COVID-19 pandemic, Sangamo is working very closely with all our clinical trial site partners to devise individualized plans to protect the safety of every patient enrolled in our studies, as well as the continued integrity of our trial data. After we have established a plan for each patient, we work with sites and IRBs to establish appropriate procedures. In some cases, trial site partners have been reducing or pausing clinical trial work to redirect capacity and resources to COVID-19 patients. At other sites, clinical trial patients are still being screened and enrolled, but may not be dosed until an appropriate time is identified.

In addition to adopting our clinical operations to this new situation, we are implementing procedures now, so that as the COVID-19 crisis subsides, we'll be able to resume operations as quickly and as efficiently as possible. To do this, we are keeping close contact with our trial site partners and continuing to identify potential patients that may be suitable for enrollment. In some cases, we're also using this time to further optimize clinical operations, processes and engage with regulatory agencies. We're also working closely with our collaboration partners to track the status of our joint development programs.

Turning now to some clinical updates commencing with SB-525 or PF-07055480, hemophilia A gene therapy. We transferred operations of the fully enrolled Phase 1/2 ALTA Study to Pfizer along with the IND at the end of last year. We're working closely together with Pfizer to identify an appropriate opportunity this year to provide an update on the results that we shared at ASH 2019 from the high-dose expansion cohort. Pfizer continues to target dosing the first patient in the Phase 3 study in H2 2020. Pfizer is working to minimize any potential disruptions to the schedule, due to the ongoing COVID-19 pandemic and continues to recruit patients into the Phase 3 lead-in study. Pfizer recently updated clinicaltrials.gov with the Phase 3 study protocol and have informed us that they plan to provide additional updates on the Phase 3 trial in due course.

Moving now to our wholly owned gene therapy, ST-920 for Fabry disease. We have successfully screened and enrolled patients into the STAAR study and we are awaiting for a safe and appropriate time to initiate dosing the first patient.

In conjunction with our partner Sanofi, we're evaluating gene-edited cell therapies for two hemoglobinopathies, ST-400 for beta thalassemia and BIVV003 for sickle cell disease. ST-400 and BIVV003 are both designed to induce the synthesis of fetal hemoglobin. This is achieved by gene-edited knock out of the erythroid-specific enhancer of the BCL11a gene, which encodes a strong repressor of the gamma globin gene. In beta thalassemia, if fetal hemoglobin is expressed at high enough levels, it may substitute for patients absent or impaired levels of beta globin. We have enrolled and dosed five patients into the THALES Study evaluating ST-400 for beta thalassemia.

In sickle cell disease, increased fetal hemoglobin synthesis may provide the patient with functional hemoglobin and help down regulate the abnormal sickle hemoglobin that results in painful sickle cell crisis and other disease features. Sanofi has also been enrolling patients into the PRECIZN-1 study evaluating BIVV003 in sickle cell disease and dosed the first patient last year. New analysis of the study's data will be shared when the two studies have accumulated a sufficient number of the patients and follow up. No additional beta thalassemia patients in the THALES Study will be treated until the data from both studies has been collected and analyzed. Sanofi, will in the meantime, continue enrolling sickle cell patients into the PRECIZN-1 study. We will look for an appropriate time to present data from both these studies at a future date.

I'd like to conclude by addressing a few programs that we are monitoring closely with regard to potential impact by COVID-19. We continue to make progress with additional regulatory approvals for the Phase 1/2 STEADFAST study, evaluating our first in human CAR-Treg cell therapy, TX200, in HLA-A2 mismatched kidney transplantation. We expect to dose the first patient in this study in 2021.

Moving on now to KITE-037, an allogeneic anti-CD19 CAR-T cell product being developed by Kite, a Gilead company. Kite has informed us that there is a potential for a COVID-related delay to the initiation of the KITE-037 clinical trial.

I will now turn the call over to Sung for an overview of the financial results. Sung?

Sung Lee -- Executive Vice President and Chief Financial Officer

Thank you, Bettina, and good afternoon, everyone. We're pleased to share our financial results for the first quarter of 2020. We reported a net loss of $42.9 million, or $0.37 per share, compared to a net loss of $42.2 million, or $0.41 per share for the same period in 2019. The revenues were $13.1 million, compared to $8.1 million for the same period in 2019.

Turning to expenses, non-GAAP operating expenses, which excludes stock compensation, were $52 million, compared to $47.4 million in 2019. The increase in operating expenses was primarily related to the Company's overall headcount growth and facilities expansion to support the advancement of Sangamo's therapeutic pipeline and manufacturing capabilities.

Moving to the balance sheet. We ended the quarter with $363 million in cash, cash equivalents and marketable securities. Following the end of Q1, we received $350 million from Biogen from the sale of stock and the upfront license fee. As Sandy mentioned earlier, we believe we have the balance sheet strength to take us through important R&D milestones, including the first potential filing of the BLA for SB-525 for hemophilia A.

Turning to 2020 full-year guidance. We are reiterating our previously shared financial guidance and anticipate non-GAAP operating expense, which excludes estimated stock compensation expense of $25 million to be in the range of $245 million to $260 million in 2020. At this time, we do not expect any material negative financial impact from COVID-19 to our operating expense guidance. We will continue to monitor the situation and provide an update in the future. In the meantime, we will continue to be good stewards of capital.

I will now turn it back to Sandy for closing remarks.

Sandy Macrae -- President and Chief Executive Officer

Thank you, Sung. This quarter marked an important milestone with the closing of the Biogen agreement, which will significantly strengthened our balance sheet and represents yet another vote of confidence in our highly differentiated zinc finger protein genomic medicine platform from a top biopharmaceutical company.

In these unprecedented times, I've observed tremendous resilience and adaptiveness from our employees. And this has kept our business moving forward, including ongoing business development discussions, continued research and technical operations in our laboratories and continued partnerships with our clinical trial sites. We feel a great sense of confidence in our business and in our ability to weather the COVID-19 crisis, due to our balance sheet strength, strategic investments in infrastructure, and to the prudent plans that we have established to facilitate our rapid return to more normal operations, as this crisis subsides.

Operator, we are ready for questions?

Operator

Thank you. [Operator Instructions] Our first question comes from Maury Raycroft with Jefferies. Your line is open.

Maury Raycroft -- Jefferies LLC -- Analyst

Hi, everyone. Thanks for taking my questions. First question is just on hemophilia A. So, with the Phase 3 trial posted to clinicaltrials.gov. Can you talk more about the design at this time, including dose, steroid use and what estimates are on how long it's going to take to enroll the study?

Sandy Macrae -- President and Chief Executive Officer

Maury, thanks for your question. As you can imagine that the Phase 3 trial is under the control and communication of Pfizer, and they will give all announcements about the design of the trial, and we want to respect that relationship with them. Everything they have told us so far guides to the trial moving ahead as planned. One of the advantages of our partnership with Pfizer is, they are a global organization that can take the trial to where the patients are available and where the COVID impact is less. So, we look forward to them sharing more information with you as the year progresses.

Maury Raycroft -- Jefferies LLC -- Analyst

Understood. Understood. And then, for Fabry, you guys have mentioned before that you had more patients screen failures than you initially expected. Just wondering if you've implemented enrollment criteria changes and have those been helping.

Sandy Macrae -- President and Chief Executive Officer

Bettina, would you be able to talk to that?

Bettina Cockroft -- Senior Vice President and Chief Medical Officer

Yes, of course. Hi, there. So, we have been looking at implementing some changes. And, as you will have noted from the communication today, we have actually enrolled patients into the Fabry study. Now, of course, during the COVID pandemic, we are being very cautious as to assessing the best timing for dosing the first subject. But we have had an uptick and that has resulted in inclusion of patients into the study.

Sandy Macrae -- President and Chief Executive Officer

And Bettina, you feel that the changes you made to the protocol have permitted that or facilitated that?

Bettina Cockroft -- Senior Vice President and Chief Medical Officer

Exactly. Absolutely, absolutely.

Maury Raycroft -- Jefferies LLC -- Analyst

Great. Okay. And then last quick one was just on, wondering if you have formalized plans to conduct a renal biopsy for Gb3 reduction in this initial part of the study. Or could that come in later on, maybe if you could just talk more about the plans are?

Sandy Macrae -- President and Chief Executive Officer

We haven't discussed our plans for the Gb3 and for renal biopsy. As you can imagine, that is a complex issue about patient benefit and the risk of a renal biopsy. We are very appreciative of the FDA trying to make medicines for Fabry, get to patients as quickly as possible by allowing registration quicker with the renal biopsy and are very aware of that and are incorporating it into our plans.

Maury Raycroft -- Jefferies LLC -- Analyst

Got it. Thank you for taking my questions.

Sandy Macrae -- President and Chief Executive Officer

Thanks, Maury. Do well.

Operator

Thank you. Our next question comes from Gena Wang of Barclays. Your line is open.

Gena Wang -- Barclays -- Analyst

Thank you for taking my questions. I have two questions. The first is regarding hemophilia A update, and second question is regarding Fabry disease. First, hemophilia A update, I understand Pfizer emphasized the importance of 18-month data. Given follow-up from last ASH, is it fair to say 4Q this year likely would be a good timing to show data? And for the Fabry disease, you did mention you enrolled several patients. Just wondering how many patients. And also, is this still possible to present initial data beginning of next year? Also, can you remind us the first dose for Fabry disease?

Sandy Macrae -- President and Chief Executive Officer

So, I'll let me take the first question before passing you on to Bettina, but warning you that we haven't talked about the first dose yet. But if I could do the hemophilia A, unfortunately, the world time moves at just the same rate, and patients are only now coming out of their 18-month point and that's very weak patients and it will take throughout the rest of the -- this and the next quarter for the majority of patients to reach their 18-month point. So, Pfizer will lead all communications as part of the deal for transition like this. You agree which company will lead all communications, and that is in Pfizer's hands and they will decide when they have data that they will share with you all. I know this is frustrating, but it's -- it has to be a single company that leads that.

And Bettina, can you talk about our enrollment in Fabry, please?

Bettina Cockroft -- Senior Vice President and Chief Medical Officer

Yes, absolutely. So, as far as Fabry is concerned, to address your last question first, we're going to be showing data after we've completed dose escalation across the three cohorts that we have in our protocol. We want to make sure that we present a mature dataset that can represent safety and efficacy of ST-920. And in terms of which doses we were planning to test, we have said low, medium and high. We will disclose specific doses at an appropriate point in the future. What I can say is, we've learned a lot about AAV6 through our SB-525 hemophilia A program and we've made protocol amendments to the Fabry program to take those learnings and also FDA guidance into account. So, we look forward to updating further on this in the future.

Gena Wang -- Barclays -- Analyst

Okay. How many patient already have enrolled?

Bettina Cockroft -- Senior Vice President and Chief Medical Officer

[Speech Overlap] I think we've not disclosed...

Sandy Macrae -- President and Chief Executive Officer

Yeah, exactly. We're not disclosing that. But we have patients enrolled. We have interest from sites and it's just a matter of us choosing when to dose the first patient. I'm sure you would agree that we need to choose wisely, because the patients will have to come in for monitoring and we want to make sure that they are safe and that their health service is not overstressed.

Gena Wang -- Barclays -- Analyst

Thank you.

Operator

Thank you. Our next question comes from Whitney Ijem of Guggenheim. Your line is open.

Whitney Ijem -- Guggenheim Securities -- Analyst

Hey, guys. Thanks for taking the questions. Wanted to follow up on Fabry. So, I guess, first, can you give us any color on the entry criteria that were adjusted, that kind of facilitated enrollment, just curious if we could learn more there?

And then the second question is on the endpoints, you mentioned you won't present data until you have a complete dataset. I guess, what does that mean in terms of follow-up and kind of what endpoints are you tracking? Or is that the 12-month kind of safety follow-up that's reflected on clin-trials? Thanks.

Sandy Macrae -- President and Chief Executive Officer

So, Whitney, thank you for your question. The criteria that we adjusted were not things about antibody criteria like gene therapy things. They were more our understanding of what Fabry patients look like onboard, the right patients to put into the study. Each time, a company like our goes into a new disease, we learn from the first few patients and Bettina and her team done an excellent job in simply understanding what patients are available.

When we say we won't talk about the study until it's complete, what we mean is that, we've gone through the -- each of the dose cohorts. And as soon as we have biochemistry data from each of the dose cohorts, the low, medium and high as Bettina has said, we will share them with you. You're absolutely right that there will be follow-on data that will look at additional parameters, including in some patients' biopsy. But we hope to be able to share the biochemistry initially and talk to you about the results of our intervention.

Whitney Ijem -- Guggenheim Securities -- Analyst

Got it. And just a quick follow-up, in terms of the biochemistry what particular endpoints, I guess, are you looking at there and what's the cut-off? I guess, is it like three months or six months of biochemistry you want to have at that higher dose to kind of be the threshold for announcing the data?

Sandy Macrae -- President and Chief Executive Officer

We haven't described that. We -- you've been with us for a long time and you understand our cautiousness in speaking too soon and waiting for the results to stabilize. So, as we can most inform you and most inform the patient community.

Whitney Ijem -- Guggenheim Securities -- Analyst

Understood. Thanks very much.

Sandy Macrae -- President and Chief Executive Officer

Thank you.

Operator

Thank you. [Operator Instructions] Our next question comes from Ritu Baral of Cowen. Your line is open.

Originally posted here:
Sangamo Therapeutics Inc (SGMO) Q1 2020 Earnings Call Transcript - The Motley Fool

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Global Gene Therapy Market 2020 Key Factors and Emerging Opportunities with Current Trends Analysis 2025 - NJ MMA News

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Approach may lead to new treatment approach for osteoarthritis, obesity

Researchers at Washington University School of Medicine in St. Louis found that gene therapy in mice helped build strength and significant muscle mass quickly, while reducing the severity of osteoarthritis. The gene therapy also prevented obesity, even when the mice were fed a high-fat diet.

Exercise and physical therapy often are recommended to help people who have arthritis. Both can strengthen muscle a benefit that also can reduce joint pain. But building muscle mass and strength can take many months and be difficult in the face of joint pain from osteoarthritis, particularly for older people who are overweight. A new study in mice at Washington University School of Medicine in St. Louis, however, suggests gene therapy one day may help those patients.

The research shows that gene therapy helped build significant muscle mass quickly and reduced the severity of osteoarthritis in the mice, even though they didnt exercise more. The therapy also staved off obesity, even when the mice ate an extremely high-fat diet.

The study is published online May 8 in the journal Science Advances.

Obesity is the most common risk factor for osteoarthritis, said senior investigator Farshid Guilak, PhD, the Mildred B. Simon Research Professor of Orthopaedic Surgery and director of research at Shriners Hospitals for Children St. Louis. Being overweight can hinder a persons ability to exercise and benefit fully from physical therapy. Weve identified here a way to use gene therapy to build muscle quickly. It had a profound effect in the mice and kept their weight in check, suggesting a similar approach may be effective against arthritis, particularly in cases of morbid obesity.

With the papers first author, Ruhang Tang, PhD, a senior scientist in Guilaks laboratory, Guilak and his research team gave 8-week-old mice a single injection each of a virus carrying a gene called follistatin. The gene works to block the activity of a protein in muscle that keeps muscle growth in check. This enabled the mice to gain significant muscle mass without exercising more than usual.

Even without additional exercise, and while continuing to eat a high-fat diet, the muscle mass of these super mice more than doubled, and their strength nearly doubled, too. The mice also had less cartilage damage related to osteoarthritis, lower numbers of inflammatory cells and proteins in their joints, fewer metabolic problems, and healthier hearts and blood vessels than littermates that did not receive the gene therapy. The mice also were significantly less sensitive to pain.

One worry was that some of the muscle growth prompted by the gene therapy might turn out to be harmful. The heart, for example, is a muscle, and a condition called cardiac hypertrophy, in which the hearts walls thicken, is not a good thing. But in these mice, heart function actually improved, as did cardiovascular health in general.

Longer-term studies will be needed to determine the safety of this type of gene therapy. But, if safe, the strategy could be particularly beneficial for patients with conditions such as muscular dystrophy that make it difficult to build new muscle.

In the meantime, Guilak, who also co-directs the Washington University Center for Regenerative Medicine and is a professor of biomedical engineering and of developmental biology, said more traditional methods of muscle strengthening, such as lifting weights or physical therapy, remain the first line of treatment for patients with osteoarthritis.

Something like this could take years to develop, but were excited about its prospects for reducing joint damage related to osteoarthritis, as well as possibly being useful in extreme cases of obesity, he said.

Tang R, Harasymowicz NS, Wu CL, Collins KH, Choi YR, Oswald SJ, Guilak F. Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet-induced obesity. Science Advances, published online May 8, 2020.

This work was supported by the Shriners Hospitals for Children, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging and the Office of the Director of the National Institutes of Health (NIH). Grant numbers AR50245, AR48852, AG15768, AR48182, AG 46927, AR073752, OD10707, AR060719, AR057235. Additional funding was provided by the Arthritis Foundation and the Nancy Taylor Foundation for Chronic Diseases.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Gene therapy in mice builds muscle, reduces fat Washington University School of Medicine in St. Louis - Washington University School of Medicine in...

PHILADELPHIA, May 07, 2020 (GLOBE NEWSWIRE) -- Passage Bio, Inc. (NASDAQ: PASG), a genetic medicines company focused on developing transformative therapies for rare, monogenic central nervous system (CNS) disorders and the Gene Therapy Program (GTP) at the University of Pennsylvania (UPenn) today announced the expansion of their collaboration agreement to include an additional five programs and extending Passage Bios period to exercise new programs for an additional three years (through 2025). Additionally, Passage Bio will fund discovery research at GTP and will receive exclusive rights, subject to certain limitations, to technologies resulting from the discovery program for Passage Bio products developed with GTP, such as novel capsids, toxicity reduction technologies and delivery and formulation improvements.

Our collaboration with the GTP gives us access not only to the best discovery, technology, and research available but also to pioneering expertise in the field of gene therapy, including pre-clinical development and manufacturing experience that will help guide our programs as we move into clinical development, said Bruce Goldsmith, Ph.D., president and chief executive officer of Passage Bio. Expanding this collaboration provides us with the opportunity to not only deepen our pipeline but also strengthen our own expertise and capabilities as we strive to develop transformative gene therapies for patients. We are tremendously proud of the progress we have accomplished to date through this partnership and look forward to continuing this momentum in the years to come.

This expansion builds upon the original collaboration, which successfully established a strong partnership between Passage and GTP. Under the expanded agreement, Passage will pay $5 million annually to Penn to fund research across numerous technology applications for gene therapy. In addition to five additional program options and an extension of the relationship through 2025, Passage will receive exclusive rights, subject to certain limitations, to IP arising from this research and related indications that are applicable to the products it develops with GTP.

The partnership between GTP and Passage Bio continues to be extremely strong and productive as we collaborate to bring our gene therapy products to patients. We are extremely excited to expand the reach of our CNS products and discovery research through this continued collaboration, said James Wilson, M.D., Ph.D. director of the Gene Therapy Program at the University of Pennsylvania and chief scientific advisor of Passage Bio. As a co-founder of the company, I am also deeply committed to the growth and success of Passage. I believe that the expansion of this strong collaboration further establishes Passage Bios leadership in gene therapy and I look forward to continuing to work with our dedicated teams to reach these shared goals of helping patients with rare, monogenic CNS disorders.

About Passage Bio Passage Bio is a genetic medicines company focused on developing transformative therapies for rare, monogenic central nervous system disorders with limited or no approved treatment options. The company is based in Philadelphia, PA and has a research, collaboration and license agreement with the University of Pennsylvania and its Gene Therapy Program (GTP). The GTP conducts discovery and IND-enabling preclinical work and Passage Bio conducts all clinical development, regulatory strategy and commercialization activities under the agreement. The company has a development portfolio of six product candidates, with the option to license eleven more, with lead programs in GM1 gangliosidosis, frontotemporal dementia and Krabbe disease.

Forward Looking StatementThis press release contains forward-looking statements within the meaning of, and made pursuant to the safe harbor provisions of, the Private Securities Litigation Reform Act of 1995, including, but not limited to: our expectations about our collaborators and partners ability to execute key initiatives and the benefits and obligations associated with our arrangements with our collaborators and partners; and the ability of our lead product candidates to treat the underlying causes of their respective target monogenic CNS disorders. These forward-looking statements may be accompanied by such words as aim, anticipate, believe, could, estimate, expect, forecast, goal, intend, may, might, plan, potential, possible, will, would, and other words and terms of similar meaning. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: our ability to develop, obtain regulatory approval for and commercialize our product candidates; the timing and results of preclinical studies and clinical trials; the risk that positive results in a preclinical study or clinical trial may not be replicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; risks associated with clinical trials, including our ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates; the occurrence of adverse safety events; failure to protect and enforce our intellectual property, and other proprietary rights; failure to successfully execute or realize the anticipated benefits of our strategic and growth initiatives; risks relating to technology failures or breaches; our dependence on collaborators and other third parties for the development of product candidates and other aspects of our business, which are outside of our full control; risks associated with current and potential delays, work stoppages, or supply chain disruptions caused by the coronavirus pandemic; risks associated with current and potential future healthcare reforms; risks relating to attracting and retaining key personnel; failure to comply with legal and regulatory requirements; risks relating to access to capital and credit markets; and the other risks and uncertainties that are described in the Risk Factors section in documents the company files from time to time with theSecurities and Exchange Commission(SEC), and other reports as filed with theSEC. Passage Bio undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

For further information, please contact:

Investors:Sarah McCabeStern Investor Relations, Inc.212-362-1200sarah.mccabe@sternir.com

Media:Emily MaxwellHDMZ312-506-5220emily.maxwell@hdmz.com

Financial Disclosure: The University of Pennsylvania and Dr. James Wilson are both co-founders of Passage Bio and hold equity interests in the company. Dr. Wilson is also the chief scientific advisor of the Company. Penn and GTP are the recipients of significant sponsored research support from the Company under research programs directed by Dr. Wilson. Penn has licensed or optioned numerous technologies to Passage Bio under an existing license and these ongoing sponsored research activities, and both Penn and Dr. Wilson stand to receive additional financial gains in the future under these licensing arrangements.

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Passage Bio Announces Expansion of Gene Therapy Collaboration with University of Pennsylvania - GlobeNewswire

Scientists at the Washington University School of Medicine in St. Louis, believe that gene therapy could one day be used as fat reducing therapy.

In a new study conducted on mice, scientists found that gene therapy helped build significant muscle mass quickly and reduced the severity of osteoarthritis in the mice without exercising more. Surprisingly, the therapy also staved off obesity, even when the mice ate an extremely high-fat diet.

Senior investigator Farshid Guilak, Ph.D., the Mildred B. Simon Research Professor of Orthopaedic Surgery and director of research at Shriners Hospitals for ChildrenSt. Louis said,Obesity is the most common risk factor for osteoarthritis. Being overweight can hinder a persons ability to exercise and benefit fully from physical therapy. Weve identified here a way to use gene therapy to build muscle quickly. It had a profound effect on the mice and kept their weight in check, suggesting a similar approach may be effective against arthritis, particularly in cases of morbid obesity.

Scientists gave 8-week-old mice a single injection of a virus conveying a gene called follistatin. The gene works to obstruct the action of a protein in muscle that keeps muscle growth in check. This empowered the mice to gain significant muscle mass without exercising more than usual.

Even without additional exercise, and while continuing to eat a high-fat diet, the muscle mass of these super mice more than doubled, and their strength nearly doubled, too. The mice also had less cartilage damage related to osteoarthritis, lower numbers of inflammatory cells and proteins in their joints, fewer metabolic problems, and healthier hearts and blood vessels than littermates that did not receive the gene therapy. The mice also were significantly less sensitive to pain.

During the study, scientists were concerned that some of the muscle growth might lead to being harmful. But, they found that heart function improved, as did cardiovascular health in general.

Although scientists think that long-term studies are required to determine the safety of this type of gene therapy, but, if safe, the strategy could be particularly beneficial for patients with conditions such as muscular dystrophy that make it challenging to build new muscle.

Guilak said,More traditional methods of muscle strengthening, such as lifting weights or physical therapy, remain the first line of treatment for patients with osteoarthritis. Something like this could take years to develop. Still, were excited about its prospects for reducing joint damage related to osteoarthritis, as well as possibly being useful in extreme cases of obesity.

Link:
Study suggests effective fat-reducing therapy - Tech Explorist

A new business intelligence report released by CMI with the title Global Gene Therapy for Rare Disease Market Research Report 2020-2027 is designed covering micro level of analysis by manufacturers and key business segments. The Global Gene Therapy for Rare Disease Market survey analysis offers energetic visions to conclude and study market size, market hopes, and competitive surroundings. The research is derived through primary and secondary statistics sources and it comprises both qualitative and quantitative detailing.

Whats keeping Kite Pharma, Inc. (Gilead Sciences, Inc.), Novartis International AG, Juno Therapeutics Inc. (Celgene Corporation), Bluebird Bio, Inc., Spark Therapeutics, Inc., uniQure N.V, Orchard Therapeutics Plc., PTC Therapeutics, Inc., and BioMarin Pharmaceutical Inc. Ahead in the Market? Benchmark yourself with the strategic moves and findings recently released by CMI.

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This report sample includesBrief Introduction to the research report.Table of Contents (Scope covered as a part of the study)Top players in the marketResearch framework (presentation)Research methodology adopted by Coherent Market Insights

Market Overview of Global Gene Therapy for Rare Disease

If you are involved in the Global Gene Therapy for Rare Disease industry or aim to be, then this study will provide you inclusive point of view. Its vital you keep your market knowledge up to date segmented by Applications and major players. If you have a different set of players/manufacturers according to geography or needs regional or country segmented reports we can provide customization according to your requirement.

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Historical year 2015 2019

Base year 2019

Forecast period** 2020 to 2027 [** unless otherwise stated]

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Regions included:

North America (United States, Canada, and Mexico)

Europe (Germany, France, UK, Russia, and Italy)

Asia-Pacific (China, Japan, Korea, India, and Southeast Asia)

South America (Brazil, Argentina, Colombia)

Middle East and Africa (Saudi Arabia, UAE, Egypt, Nigeria, and South Africa)

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Important Features that are under offering & key highlights of the report:

Detailed overview of Gene Therapy for Rare Disease market

Changing market dynamics of the industry

In-depth market segmentation by Type, Application etc

Historical, current and projected market size in terms of volume and value

Recent industry trends and developments

Competitive landscape of Gene Therapy for Rare Disease market

Strategies of key players and product offerings

Potential and niche segments/regions exhibiting promising growth

A neutral perspective towards Gene Therapy for Rare Disease market performance

Market players information to sustain and enhance their footprint

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Major Highlights of TOC:

Chapter One: Global Gene Therapy for Rare Disease Market Industry Overview

1.1 Gene Therapy for Rare Disease Industry

1.1.1 Overview

1.1.2 Products of Major Companies

1.2 Gene Therapy for Rare Disease Market Segment

1.2.1 Industry Chain

1.2.2 Consumer Distribution

1.3 Price & Cost Overview

Chapter Two: Global Gene Therapy for Rare Disease Market Demand

2.1 Segment Overview

2.1.1 APPLICATION 1

2.1.2 APPLICATION 2

2.1.3 Other

2.2 Global Gene Therapy for Rare Disease Market Size by Demand

2.3 Global Gene Therapy for Rare Disease Market Forecast by Demand

Chapter Three: Global Gene Therapy for Rare Disease Market by Type

3.1 By Type

3.1.1 TYPE 1

3.1.2 TYPE 2

3.2 Gene Therapy for Rare Disease Market Size by Type

3.3 Gene Therapy for Rare Disease Market Forecast by Type

Chapter Four: Major Region of Gene Therapy for Rare Disease Market

4.1 Global Gene Therapy for Rare Disease Sales

4.2 Global Gene Therapy for Rare Disease Revenue & market share

Chapter Five: Major Companies List

Chapter Six: Conclusion

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Key questions answered

o Who are the Leading key players and what are their Key Business plans in the Global Gene Therapy for Rare Disease market?

o What are the key concerns of the five forces analysis of the Global Gene Therapy for Rare Disease market?

o What are different prospects and threats faced by the dealers in the Global Gene Therapy for Rare Disease market?

o What are the strengths and weaknesses of the key vendors?

Thanks for reading this article; you can also get individual chapter wise section or region wise report version like North America, Europe or Asia.

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Gene Therapy for Rare Disease Market 2020 Coronavirus (Covid-19) Business Impact 2026 Growth Trends by Manufacturers, Regions, Type and Application,...

PTC Therapeutics is acquiring Censa Pharmaceuticals in a cash and stock deal. PTC, based in South Plainfield, New Jersey, focuses on rare diseases. Censa, based in Wellesley, Massachusetts, is developing CNSA-001 for phenylketonuria and other metabolic diseases.

Under the terms of the deal, PTC is paying Censa $10 million in cash and up to 850,000 shares of PTC common stock, which as of Tuesday, May 5, was trading at $48 per share, totaling about $41 million. In addition, there are development and regulatory milestones for the two most advanced programs that can reach $217.5 million. There is also receipt of a priority review voucher and $30 million to be paid in either cash or PTC common stock after completing the enrollment of a Phase III clinical trial for CNSA-001, $109 million in development and regulatory milestones for each extra indication for CNSA-001, net sales milestones up to about $160 million and a contingent value payment of a percentage of annual net sales in the single to low double digits.

Results from a Phase II clinical trial of CNSA-001 demonstrated significant and clinically relevant reductions in phenylalanine levels compared to current first-line treatment, said Stuart W. Peltz, PTCs chief executive officer. We believe that CNSA-001 has the potential to address the majority of PKU patients whose condition is not adequately managed by current treatments. We look forward to initiating a Phase III study in PKU so that patients diagnosed with this devastating condition can have a new oral treatment option as soon as possible.

Phenylketonuria (PKU) is an inborn metabolic disorder that results in decreased metabolism of the amino acid phenylalanine. If untreated, it can cause intellectual disability, seizures, behavioral issues, and mental disorders. It is caused by a mutation in the gene that codes for the enzyme needed to metabolize phenylalanine. Patients with PKU must eat a diet that limits phenylalanine, found mostly in protein.

There are two drugs, both commercialized by BioMarin Pharmaceutical, approved for PKU. Sapropterin hydrochloride (Kuvan), an oral formulation, was approved in 2007 with a diet low in phenylalanine. In a Phase II trial, Censas drug was superior to Kuvan.

BioMarins Palynziq (pegvaliase-pqpz) was approved in 2018 by the U.S. Food and Drug Administration (FDA). It is an injectable enzyme therapy approved for adults with PKU whose blood phenylalanine concentrations remain high on current treatment. BioMarin planned to begin clinical testing of a gene therapy for the disease this year, but the COVID-19 pandemic has delayed the launch, although the company indicates it hopes to begin in the second half of 2020.

CNSA-001 is an oral formulation of synthetic sepiapterin, a precursor to intracellular tetrahydrobiopterin. Intracellular tetrahydrobiopterin is a critical enzymatic cofactor involved in the metabolism and synthesis of various metabolic products.

PTCs pipeline includes early research in gene therapy, nonsense mutation, splicing and oncology. The therapies are focused on Huntingtons disease, Angelman syndrome, relapsed/refractory acute leukemias, ovarian cancer and others. The company markets Emflaza, a treatment for Duchenne muscular dystrophy (DMD) in the U.S., and markets another DMD drug, Translarna, in Europe. It also markets Tegsedi for polyneuropathy of hereditary transthyretin-mediated amyloidosis in Latin America.

PTC, with Roche, is awaiting an approval by the FDA this year for risdiplam for spinal muscular atrophy (SMA).

I am proud of the team at Censa and its achievements to date demonstrating the potential role of CNSA-001 in treating diseases of the BH4 pathway, said Jonathan Reis, president and chief executive officer of Censa. It is the right time to have an excellent fully integrated, patient-focused biotechnology organization like PTC Therapeutics take over the late-stage development of CNSA-001 so that this promising compound becomes available to patients in the near future.

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PTC Therapeutics to Acquire Censa for $10 Million in Cash, $41 Million in Stock and More - BioSpace

The smid-cap biotech earnings deluge hit Wall Street in the week ended May 9, positively impacting the stocks in the sector. The iShares NASDAQ Biotechnology Index (NASDAQ: IBB) gained about 6% for the week.

Large-cap pharma names AstraZeneca plc (NYSE: AZN) and Novartis AG (NYSE: NVS) received FDA nods for their heart failure and lung cancer therapies, respectively. After receiving emergency use authorization from the FDA in the U.S., Gilead Sciences, Inc.'s (NASDAQ: GILD) remdesivir obtained full regulatory approval in Japan.

Moderna Inc (NASDAQ: MRNA) received the OK toproceedwith the Phase 2 trial of its mRNA coronavirus vaccine candidate mRNA-1273.

The following are the key events and catalysts that biotech investors need to watch in the coming week.

Clovis Oncology Inc (NASDAQ: CLVS) awaits the FDA nod for an expanded indication for its cancer therapy Rubraca. The sNDA seeks approval of Rubraca as a monotherapy treatment for patients with BRCA1/2-mutant recurrent, metastatic castrate-resistant prostate cancer.

Abeona Therapeutics Inc (NASDAQ: ABEO) is due to present updated interim results from the Transpher A and Transpher B studies, Phase 1/2 trials of ABO-102 and ABO-101, respectively, in mucopolysaccharidosis type IIIA, aka as Sanfilippo syndrome type.

Rocket Pharmaceuticals Inc (NASDAQ: RCKT will present updated data from Phase 1/2 FANCOLEN-I study, which is evaluating the safety and efficacy of infusion of autologous CD34 + cells transduced with a lentiviral vector carrying the FANCA gene in patients with Fanconi anemia subtype A, and updates from the Phase 1 LAD-I study that is evaluating its investigational gene therapy RP-L201 to treat severe Leukocyte Adhesion Deficiency-I.

Avrobio Inc (NASDAQ: AVRO) is scheduled to make an oral presentation on new data from the Phase 2 trial of AVR-RD-01 for Fabry (Wednesday). The company will also make an oral presentation of new data from the collaborator-sponsored Phase 1/2 clinical trial of AVR-RD-04 in cystinosis. Another oral presentation on new data from a preclinical research program for a gene therapy for Pompe disease is also scheduled for Wednesday.

Ultragenyx Pharmaceutical Inc (NASDAQ: RARE) is due to present updated data from the first three cohorts of a Phase 1/2 study of DTX301 in treating ornithine transcarbamylase deficiency (Wednesday). The company will also present updated data from the confirmatory cohort from a Phase 1/2 study of DTX401 in glycogen storage disease Type 1a (Friday).

Pfizer Inc. (NYSE: PFE) will present Phase 1b data for PF-06939926 in Duchenne muscular dystrophy on Friday.

Krystal Biotech Inc (NASDAQ: KRYS) will present a poster on KB407, an HSV-1 based gene therapy vector, for the treatment of cystic fibrosis.

See Also: Gilead Works To 'Maximize Global Supply' Of Coronavirus Candidate Remdesivir Amid Threat Of Patent Loss

Genocea Biosciences Inc (NASDAQ: GNCA) will host a KOL symposium with a live Q&A for analysts and investors to reflect on the progress of the T cell therapy landscape and provide an in-depth profile of GEN-011 Genocea's neoantigen cell therapy. (Tuesday)

Krystal Biotech is due to present at the SID meeting withresults froma Phase 1/2 study of in vivo gene therapy KB105 for treating autosomal recessive congenital ichthyosis as well as results of a Phase 1/2 trial that is evaluating in vivo correction of dystrophic epidermolysis bullosa by direct cutaneous COL7A1 gene replacement.

Caladrius Biosciences Inc (NASDAQ: CLBS) will present at the SCAI meeting Thursday with full data from the ESCaPE-CMD study of CLBS16 for the treatment of coronary microvascular dysfunction.

Constellation Pharmaceuticals Inc (NASDAQ: CNST) said abstracts of a presentation due at the June 11-14 European Hematology Association meeting will be made available Thursday. The abstract pertains to an interim update from the MANIFEST Phase 2 study that is evaluating CPI-0610 in myelofibrosis.

Auris Medical Holding Ltd (NASDAQ: EARS) is due to release top-line data in early May from the Phase 1b trial that is evaluating AM-201 in healthy volunteers. AM-201 is the company's investigational drug for the prevention of antipsychotic-induced weight gain and somnolence.

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ORIC Pharmaceuticals Inc (NASDAQ: ORIC)

2020 Benzinga.com. Benzinga does not provide investment advice. All rights reserved.

Excerpt from:
The Week Ahead In Biotech: Virtual Conference Presentations, Clovis PDUFA Date In The Spotlight - Benzinga

SHANGHAI, China, May 10, 2020 (GLOBE NEWSWIRE) -- Burning Rock and Illumina (NASDAQ: ILMN), a global leader in gene sequencing and array-based technologies, jointly announced today that they are joining forces to promote the development and standardization of NGS-based cancer therapy selection in China based on Illuminas NextSeqTM 550Dx system.

In 2015, Illuminas sequencing technology and Burning Rocks development and commercial capabilities were for the first time combined, providing Chinas precision oncology market with advanced NGS-based cancer therapy selection solutions in the past five years. In 2020, as the first genetic testing company in China to achieve development of in vitro diagnostic (IVD) tests for both circulating tumor DNA (ctDNA) and tissue based on the NextSeqTM 550Dx system agreement with Illumina, Burning Rock will further expand and deepen the application of NGS technologies in the field of cancer therapy selection.

The value of NGS application in precision medicine and companion diagnostics has been widely recognized by clinical experts and cancer patients. Compared with traditional genetic testing methods, NGS-based cancer therapy selection allows patients to understand the mutation of multiple genes related to cancer treatment, providing doctors and patients with one-stop targeted therapy and immunotherapy drugs testing solutions, ultimately saving time and preserving samples.

In July 2018, Burning Rocks innovative product "Human EGFR / ALK / BRAF / KRAS gene mutation detection kit (reversible end termination sequencing method)" based on Illumina sequencing system became the first NGS-based reagent kit to be approved by National Medication Products Administration (NMPA). Since then, tumor NGS testing can be officially used in Chinese hospitals. In the future, Burning Rock will continue to seek NMPA approvals for its IVD products based on NextSeqTM 550Dx and other sequencing systems to promote the implementation of tumor NGS products in hospitals and benefit more cancer patients.

Through our long-term, close and pleasant cooperation with Illumina, we have delivered the world's leading NGS-based therapy selection solutions for clinical oncology, and improved the development and application of NGS-based cancer therapy selection in China. said Mr. Han Yusheng, founder and CEO of Burning Rock. Today we are delighted to announce that Burning Rock and Illumina will further deepen cooperation based on the NextSeqTM 550Dx system, to provide more high-quality molecular diagnostic solutions for clinical oncology treatment and promote the standardization of NGS-based cancer therapy selection in China.

Burning Rock is one of the leading precision oncology companies in China, said Joydeep Goswami, Senior Vice President of Corporate Development and Strategic Planning at Illumina, said. I am pleased to see that during the close cooperation with Illumina in the past five years, Burning Rock has continuously developed tumor diagnosis solutions that meet the needs of the local market. The new agreement is a testament to our strong cooperation in the past, and also the beginning of a more in-depth cooperation.

Li Qing, General Manager of Greater China at Illumina, said: Burning Rock has brought hope to countless Chinese patients by providing a series of tumor molecular diagnostic solutions. And we are very happy to be involved. In the future, I firmly believe that genetic testing technology will further change the current treatment paradigm for cancer and provide critical support to conquer this disease at an early date.

About Burning RockBurning Rock, whose mission is to Guard Life via Science, focuses on the application of next generation sequencing (NGS) technology in the field of precision oncology. Its business consists of i) NGS-based therapy selection testing for late-stage cancer patients, with the leading market share in China and over 185,000 tissue and liquid-based tests completed cumulatively, and ii) NGS-based cancer early detection, which has moved beyond proof-of-concept R&D into the clinical validation stage.

About IlluminaIllumina is improving human health by unlocking the power of the genome. Our focus on innovation has established us as the global leader in DNA sequencing and array-based technologies, serving customers in the research, clinical and applied markets. Our products are used for applications in the life sciences, oncology, reproductive health, agriculture and other emerging segments. To learn more, visit http://www.illumina.comand follow @illumina.

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Burning Rock deepens cooperation with Illumina to promote development and standardization of NGS-based cancer therapy selection in China -...

Research report on Viral Vector Manufacturing Market size | Industry Segment by Applications, by Type, Regional Outlook, Market Demand, Latest Trends, Viral Vector Manufacturing Industry Share & Revenue by Manufacturers, Company Profiles, Growth Forecasts 2025. Analyzes current market size and upcoming 5 years growth of this industry.

Report Covers Global Industry Analysis, Size, Share, CAGR, Trends, Forecast And Business Opportunity.

Download Premium Sample Copy Of This Report: https://brandessenceresearch.biz/Request/Sample?ResearchPostId=473&RequestType=Sample

Global Viral Vector Manufacturing Market to reach USD 1.24 billion by 2025.

Global Viral Vector Manufacturing Market valued approximately USD 225.44 million in 2016 is forecasted to grow with a healthy growth rate of more than 20.84% over the forecast period 2018-2025. The major factors speculated to augment the markets are availability of funding for the advancement of gene therapy, and increasing frequency of cancer, genetic disorders & infectious diseases. The risk of undesirable outcomes including mutagenesis are major challenges for the global market. Viral vectors are tools commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism (in vivo) or in cell culture (in vitro). Molecular biologists first harnessed this machinery in the 1970s.Global Viral Vector Manufacturing Market is segmented based on Type, Disease, Application, and Industry. The Adeno-associated subsegment segment of Type segment is forecasted to grow with highest CAGR while the Cancers subsegment is expected to dominate in terms of market share. Gene Therapy subsegment is also expected to achieve highest growth rate whereas Biopharmaceutical & Pharmaceutical Companies subsegment would remain dominant in market share size.The regional analysis of Global Viral Vector Manufacturing Market is considered for the key regions such as Asia Pacific, North America, Europe, Latin America and Rest of the World. North America is the leading region across the world. Whereas, owing to rising no. of research activities in countries such as China, India, and Japan, Asia Pacific region is also expected to exhibit higher growth rate / CAGR over the forecast period 2018-2025. The objective of the study is to define market sizes of different segments & countries in recent years and to forecast the values to the coming eight years. The report is designed to incorporate both qualitative and quantitative aspects of the industry within each of the regions and countries involved in the study. Furthermore, the report also caters the detailed information about the crucial aspects such as driving factors & challenges which will define the future growth of the market. Additionally, the report shall also incorporate available opportunities in micro markets for stakeholders to invest along with the detailed analysis of competitive landscape and product offerings of key players. The detailed segments and sub-segment of the market are explained below:

By Type:

oAdenoviraloRetroviraloAdeno-associatedoOthers

By Disease:

oGenetic DisordersoInfectious diseasesoCancersoOthers

By Application:

oVaccinologyoGene Therapy

By End-Use:

oResearch InstitutesoBiopharmaceutical & Pharmaceutical CompaniesoOthers

By Regions:oNorth AmericaoU.S.oCanadaoEuropeoUKoGermanyoAsia PacificoChinaoIndiaoJapanoLatin AmericaoBraziloMexicooRest of the World

Furthermore, years considered for the study are as follows:

Historical year 2015, 2016Base year 2017Forecast period 2018 to 2025

The industry is seeming to be fairly competitive. Some of the leading market players CGT Catapult, Lonza, uniQure, Merck, Cobra Biologics, Oxford BioMedica, FUJIFILM Diosynth Biotechnologies, Novasep, Spark Therapeutics, Kaneka Eurogentec, Brammer Bio, Massbiologics, Finvector Vision Therapies, Regenxbio, Thermo Fisher Scientific, Inc., Sanofi, Shenzhen SiBiono GeneTech Co., Ltd., and so on. The fierce competitiveness has made these players spend in product developments to improve the customers requirements.

Target Audience of the Viral Vector Manufacturing Market Study:

oKey Consulting Companies & AdvisorsoLarge, medium-sized, and small enterprisesoVenture capitalistsoValue-Added Resellers (VARs)oThird-party knowledge providersoInvestment bankersoInvestors

Have Any Query Or Specific Requirement? : https://brandessenceresearch.biz/Request/Sample?ResearchPostId=473&RequestType=Customization

Table of Content:

Market Overview:The report begins with this section where product overview and highlights of product and application segments of the Global Viral Vector Manufacturing Market are provided. Highlights of the segmentation study include price, revenue, sales, sales growth rate, and market share by product.

Competition by Company:Here, the competition in the Worldwide Global Viral Vector Manufacturing Market is analyzed, By price, revenue, sales, and market share by company, market rate, competitive situations Landscape, and latest trends, merger, expansion, acquisition, and market shares of top companies.

Company Profiles and Sales Data:As the name suggests, this section gives the sales data of key players of the Global Viral Vector Manufacturing Market as well as some useful information on their business. It talks about the gross margin, price, revenue, products, and their specifications, type, applications, competitors, manufacturing base, and the main business of key players operating in the Global Viral Vector Manufacturing Market.

Market Status and Outlook by Region:In this section, the report discusses about gross margin, sales, revenue, production, market share, CAGR, and market size by region. Here, the Global Viral Vector Manufacturing Market is deeply analyzed on the basis of regions and countries such as North America, Europe, China, India, Japan, and the MEA.

Application or End User:This section of the research study shows how different end-user/application segments contribute to the Global Viral Vector Manufacturing Market.

Market Forecast:Here, the report offers a complete forecast of the Global Viral Vector Manufacturing Market by product, application, and region. It also offers global sales and revenue forecast for all years of the forecast period.

Research Findings and Conclusion:This is one of the last sections of the report where the findings of the analysts and the conclusion of the research study are provided.

About Us:

We publish market research reports & business insights produced by highly qualified and experienced industry analysts. Our research reports are available in a wide range of industry verticals including aviation, food & beverage, healthcare, ICT, Construction, Chemicals and lot more. Brand Essence Market Research report will be best fit for senior executives, business development managers, marketing managers, consultants, CEOs, CIOs, COOs, and Directors, governments, agencies, organizations and Ph.D. Students.

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COVID-19 pandemic Viral Vector Manufacturing Market Size Share Analysis and System Production (2020-2025) - Cole of Duty

For people with rare diseases, a single gene therapy treatment could restore normal function and alleviate the burden of ongoing care, as Dr Ian Winburn tells Kennas Fitzsimons

Dr Ian Winburn

Gene therapy is the next generation of medicine that targets the underlying cause of genetic diseases. It has the potential to offer patients a really transformational clinical benefit and improve quality of life.

Thats according to Dr Ian Winburn, Global Medical Lead, Haemophilia, Endocrine and Inborn Errors of Metabolism (IEM), Rare Diseases, Pfizer Biopharmaceuticals Group. Dr Ian Winburn, Global Medical Lead, Haemophilia, Endocrine and IEM, Pfizer Biopharmaceuticals Group, pictured right during his presentation on gene therapy at BioPharma Ambition held in Dublin Castle on March 4. Pic: Conor McCabe Photography.

Formerly a clinician in the UK National Health Service (NHS), Dr Winburn trained in general surgery and completed a PhD on novel drug discovery in renal transplantation before moving into industry 10 years ago, where he worked in the area of inflammation and immunology before leading the European haemophilia team.

Dr Winburn is now working to develop innovative gene therapies with the potential to restore normal function to patients with rare diseases, possibly with just a single treatment, changing the way people manage their disease.

Gene therapy: What is it?Gene therapy uses genes as medicine. It works by introducing functioning copies of missing or defective genes into the body and can target the underlying cause of a disease at the cellular level.

There are various types of gene therapies, such as the gene editing technique, CRISPR (clustered regularly interspaced short palindromic repeats), as well as epigenetic approaches that look at ways in which genes may be turned on or turned off.

Pfizer Rare Disease is focusing on an in-vivo approach that utilises a recombinant adeno-associated virus (AAV) to deliver the gene therapy.

This approach works by targeting the missing or non-functional gene in an individuals DNA and adding a copy of it with a functioning gene that, in turn, produces a functioning protein.

The functioning gene serves as a blueprint for the tissue to create the missing or non-functioning protein that is causing a disease.

Dr Winburn said: Gene therapy is in the branch of genetic medicine, where you can think about approaches that look to add a gene to a host cell, and that gene goes on and codes for a protein. That protein its coding for can replace a missing protein. So, in the example of haemophilia, where theres a missing factor VIII or factor IX clotting factor, that protein that is either missing or is faulty could be essentially administered through a gene therapy. A gene is added to a host cell that codes for the factor VIII or factor IX and therefore replaces that protein.

The functioning gene is delivered directly to the targeted cells by means of a highly specialised viral vector. This vector, effectively, is the package that contains the gene. In simple terms, it can be likened to the cardboard boxes that online retailers use to ship products.

The manufactured vectors are protein shells modelled after viruses in which all infectious viral components have been removed, and a functioning gene is added. Different viral vectors are used to reach specific tissues in the body, such as the liver or muscle.

VectorVector is a great word because vector describes a direction, by definition, and the other way we can think about vector is a vector often carries something. There are a few approaches you can use to develop a vector. We have embraced an AAV vector that has the capacity to deliver the transgene, the gene that is going to be added to the host somatic cell. In the case of haemophilia, it is targeted at the liver, Dr Winburn says.

Rare diseases focusAbout 280 million people worldwide live with a genetic disease, and more than 80 per cent of rare diseases are genetic in origin, according to Pfizer. For people born with rare diseases, the burden of disease management can be huge. Treatment is often ongoing and may be lifelong. Gene therapy could enable patients to live without the need for ongoing treatment. This raises the prospect of relief not only from symptoms but also from the burden of disease management.

Dr Winburn elaborates on the reasons why gene therapy approaches are currently focused specifically on rare diseases that have single-gene alterations.

It tends to be rare genetic diseases that are monogenic in nature Some of the more common diseases are very much multifactorial in origin: there may be a genetic component but there are other aspects to their aetiology rather than these single, monogenic conditions that gene therapy really lends itself to.

The other aspect is that these are areas of huge unmet medical need. Often, there isnt a high standard of care with either medicines or clinical interventions that are ultimately influencing the progression and the symptoms of the disease, he says.

A lot of rare diseases often affect children by the very nature of their being of genetic origin. In some cases, children dont get the opportunity to grow up into adulthood because of these rare diseases. Having the opportunity to develop medicines where there is such a high level of unmet need and, ultimately, impact in a positive way the lives of families and their carers is a huge motivation.

Dr Winburn adds that rare diseases, collectively, are common. There are approximately 7,000 rare diseases, and the majority of these are of genetic origin. Gene therapy offers a groundbreaking technology to address these genetic diseases that have historically not had particularly strong standards of care or clinical treatment paradigms offered to them.

Gene therapy for haemophiliaPeople with the genetic disorder of haemophilia have insufficient levels of a clotting factor that helps to stop bleeding. Consequently, they bleed for longer than other people. The disease is typically treated through infusions of the missing clotting factor, with patients undergoing regular replacement therapy. Gene therapy could revolutionise this treatment model.

Its really important to put yourself in the position of a parent who has a young child who has haemophilia, Dr Winburn says.

Often, this disorder of coagulation that results in spontaneous bleeding due to the lack of functioning clotting factor first presents as early as the age of two, classically when children are becoming toddlers, when they start bumping into things and they develop bruising and the likes.

That alerts their parents attention to the possibility that there is something wrong with their clotting system and they [undergo] clinical tests and a diagnosis is made. Or, because its a genetic condition, it may run in families and parents are aware of the possibility of their newborn having haemophilia.

But if you are diagnosed, for example, at the age of two, it means that the mainstay of treatment is factor replacement. So, that commonly is an intravenous infusion possibly two to three times a week, possibly once a week, or once every other week, depending on whether its haemophilia A or B and what type of medicine is being prescribed. But its certainly frequent treatments. Again, if you put that back to a parent wholl be doing those infusions from the age of two or three that lifelong need and burden is huge.

While factor replacement enables children to live a full and active life to a degree, children with haemophilia may not necessarily get the opportunity to engage in all the activities children typically partake in as they are growing up, such as contact sports, Dr Winburn says.

There is this ongoing, lifelong burden of treatment. As those boys transition into adulthood, they often take responsibility for that and if they dont get their treatment then they will bleed spontaneously into their joints, they get problems with haemarthropathy, causing damage.

Ultimately, the incidence of joint damage and joint replacement surgeries is incredibly significant in the haemophilia population. And that is often despite optimal prophylaxis, where its being prescribed.

So, when you think about gene therapy, this is a single, one-off treatment with the potential to alleviate the need for regular infusion for a patient.

Not all patients will be eligible for a gene therapy or are being studied in gene therapy trials. This is not going to be something thats available for everybody. But for those that are eligible, and ultimately in disease where a gene therapy has been licensed by the regulator, this really does have the potential to massively impact their lives and give them a sense of normality that they havent necessarily had up until that point in time.

Future expectationsWhile gene therapy holds promise for many people with genetic diseases, it will not be an appropriate solution for every patient. The potential risks and benefits of gene therapy will be fully established through clinical trial programmes and with continued research and evaluation.

Patient safety and suitability are always primary considerations in the development of new treatments as they progress from preclinical and clinical testing through regulatory approval to potential commercial distribution. Dr Winburn stresses that, as regards the development of new gene therapies, patient safety is paramount.

Safety is always at the forefront of our thinking, it is the heart of our clinical trial programmes, it is the heart of all our regulatory work.

It is an ongoing process around evaluating safety, and particularly long-term safety, and there is a critical importance for all patients that ultimately receive a gene therapy to be followed up long-term within registries, within clinical databases, so that we can monitor and evaluate long-term safety. All our trials are designed so that safety outcomes are critically part of it and its something that we are ever watchful of.

For some patients, gene therapy is already a reality. There are currently a few rare diseases for which gene therapies are available as therapeutic options in Europe, and Dr Winburn anticipates that there may be up to 30 approved by 2023.

There is a rare congenital cause of blindness that currently has a gene therapy available and similarly a rare neurological condition that affects children also has a gene therapy available, thats spinal muscular atrophy (SMA). There is also a gene therapy for beta thalassaemia that has recently been approved and is available within Europe. In terms of haemophilia, the first gene therapy is currently under review in Europe.

It may be premature to imagine a scenario whereby gene therapy is used to treat chronic diseases more generally, but in terms of future applications for these emerging technologies it is a case of watch this space.

This is an area where we are definitely in breakthrough technology. At this moment in time, our focus has been on rare diseases. There is, of course, an interest in understanding what is possible with gene therapy in terms of where it could be utilised, Dr Winburn says.

I dont want to provide any false hopes, but I think aspirationally, there is a hope that this could certainly impact many patients and their families in a positive way.

In association with Pfizer Biopharmaceuticals Group.

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Gene therapy: The 'next generation' of medicine - Irish Medical Times

publication date: May. 8, 2020

FDA has granted accelerated approval to Tabrecta (capmatinib) for adult patients with metastatic non-small cell lung cancer whose tumors have a mutation that leads to mesenchymal-epithelial transition exon 14 skipping as detected by an FDA-approved test.

Tabrecta is the first FDA-approved therapy to treat NSCLC with specific mutations (those that lead to mesenchymal-epithelial transition or MET exon 14 skipping).

Tabrecta is sponsored by Novartis.

FDA also approved the FoundationOne CDx assay (Foundation Medicine, Inc.) as a companion diagnostic for Tabrecta. Most patients had tumor samples that were tested for mutations that lead to MET exon 14 skipping using local tests and confirmed with the F1CDx, which is a next-generation sequencing based in vitro diagnostic device capable of detecting several mutations, including mutations that lead to MET exon 14 skipping.

Lung cancer is increasingly being divided into multiple subsets of molecularly defined populations with drugs being developed to target these specific groups, Richard Pazdur, director of the FDA Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDAs Center for Drug Evaluation and Research, said in a statement. Tabrecta is the first approval specifically for the treatment of patients with non-small cell lung cancer whose tumors have mutations that lead to MET exon 14 skipping. This patient population now has an option for a targeted therapy, which they didnt have prior to today.

Efficacy was demonstrated in the GEOMETRY mono-1 trial (NCT02414139), a multicenter, non-randomized, open-label, multicohort study enrolling 97 patients with metastatic NSCLC with confirmed MET exon 14 skipping. Patients received Tabrecta 400 mg orally twice daily until disease progression or unacceptable toxicity.

The main efficacy outcome measures were overall response rate (ORR) determined by a blinded independent review committee using RECIST 1.1 and response duration. Among the 28 treatment-nave patients, the ORR was 68% (95% CI: 48, 84) with a response duration of 12.6 months (95% CI: 5.5, 25.3). Among the 69 previously treated patients, the ORR was 41% (95% CI: 29, 53) with a response duration of 9.7 months (95% CI: 5.5, 13.0).

FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma

FDA has approved daratumumab and hyaluronidase-fihj (Darzalex Faspro) for adult patients with newly diagnosed or relapsed/refractory multiple myeloma. This new product allows for subcutaneous dosing of daratumumab.

Darzalex Faspro is sponsored by Janssen Biotech Inc.

Daratumumab and hyaluronidase-fihj is approved for the following indications that intravenous daratumumab had previously received:

in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant,

in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy,

in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy,

as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.

Efficacy of daratumumab and hyaluronidase-fihji (monotherapy) was evaluated in COLUMBA (NCT03277105), an open-label non-inferiority trial randomizing 263 patients to daratumumab and hyaluronidase-fihj and 259 to intravenous daratumumab (daratumumab IV). The trials co-primary endpoints were overall response rate and pharmacokinetic endpoint of the maximum Ctrough on cycle 3, day 1 pre-dose. Daratumumab and hyaluronidase-fihj was non-inferior to daratumumab IV in evaluating these two endpoints.

The ORR was 41.1% for daratumumab and hyaluronidase-fihj and 37.1% for daratumumab IV with a risk ratio of 1.11 (95% CI: 0.89, 1.37). The geometric mean ratio comparing daratumumab and hyaluronidase-fihj to daratumumab IV for maximum Ctrough was 108% (90% CI: 96,122).

Efficacy of daratumumab and hyaluronidase-fihj in combination with VMP (D-VMP) was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi-cohort, openlabel trial. Eligible patients were required to have newly diagnosed multiple myeloma and were ineligible for transplant. The major efficacy outcome measure, ORR, was 88.1% (95% CI: 77.8, 94.7).

Efficacy of daratumumab and hyaluronidase-fihj in combination with Rd (D-Rd) was evaluated in a single-arm cohort of this trial. Eligible patients had received at least one prior line of therapy. ORR was 90.8% (95% CI: 81.0, 96.5).

FDA accepts NDA for CC-486 in AML indication

FDA has accepted a New Drug Application for CC-486, an investigational oral hypomethylating agent, for the maintenance treatment of adult patients with acute myeloid leukemia who achieved complete remission, or CR with incomplete blood count recovery, following induction therapy with or without consolidation treatment, and who are not candidates for, or who choose not to proceed to, hematopoietic stem cell transplantation.

CC-486 is sponsored by Bristol Myers Squibb. FDA granted the application Priority Review and set a Prescription Drug User Fee Act goal date of Sept. 3, 2020.

The NDA submission was based on the efficacy and safety results of the phase III QUAZAR AML-001 study, which met the primary endpoint of improved overall survival for patients receiving AML maintenance treatment with CC-486 versus placebo.

Often, newly diagnosed adult patients with AML achieve a complete response with induction therapy, however many patients will relapse and experience a poor outcome. Patients in remission are seeking treatment options that decrease the likelihood of relapse and extend overall survival, Noah Berkowitz, senior vice president of Global Clinical Development, Hematology, at Bristol Myers Squibb, said in a statement.

CC-486 is an investigational therapy that is not approved for any use in any country.

Caris Life Sciences submits two PMA applications to FDA for whole exome and whole transcriptome sequencing

Caris Life Sciences has submitted two Pre-Market Approval applications for MI Exome CDx and MI Transcriptome CDx to FDA.

MI Exome CDx, whole exome sequencing (DNA), and MI Transcriptome CDx, whole transcriptome sequencing (RNA), are precision medicine assays that include key companion diagnostic biomarkers with therapy claims, and detect all classes of alterations including genomic signatures for microsatellite instability, tumor mutation burden, and loss of heterozygosity.

MI Exome CDx is a next-generation sequencing-based test utilizing DNA isolated from formalin-fixed paraffin embedded tumor tissue specimens for the qualitative detection of genomic alterations. MI Exome CDx can identify genetic variants (single nucleotide variants, insertions and deletions), copy number alterations, MSI, TMB and LOH.

MI Transcriptome CDx is a next-generation sequencing-based test that utilizes RNA isolated from formalin-fixed paraffin embedded tumor tissue specimens for the qualitative detection of genomic and transcriptomic alterations. MI Transcriptome CDx is a broad, multi-gene panel utilized to identify gene fusions, transcript variants, genetic variants (single nucleotide variants, insertions and deletions), and gene expression changes. FDA granted MI Transcriptome CDx received Breakthrough Device designation in 2019.

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FDA approves Tabrecta, first targeted therapy to treat metastatic NSCLC - The Cancer Letter

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Orchard Therapeutics(NASDAQ:ORTX)Q12020 Earnings CallMay 9, 2020, 8:30 p.m. ET

Operator

Ladies and gentlemen, thank you for standing by, and welcome to the Orchard Therapeutics First Quarter 2020 Investor Conference Call. [Operator Instructions]

I would now like to hand off the conference over to your speaker today, Renee Leck, Director of Investor Relations. Please go ahead, ma'am.

Renee T. Leck -- Director, Investor Relations

Thanks, Sonia. Good morning, everyone, and welcome to Orchard's First Quarter 2020 Investor Call. You can access the slides for today's call by going to the Investors section of our website, orchardtx.com.

Before we get started, I'd like to remind everyone that statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risk factors and uncertainties, and including those set forth in our annual 10-K filed with the SEC and any other filings we may make. In addition, any forward-looking statements made on this call represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements.

And with that, I'll turn the call over to our CEO, Bobby Gaspar.

Bobby Gaspar, M.D., Ph.D. -- Chief Executive Officer

Thanks, Renee. Hello, everyone, and welcome. I'd like to start by first acknowledging the tremendous efforts of our organization and our partners in the healthcare field to ensure patients in need continue to receive care during this difficult time. Thank you, everyone. The last few weeks have been an important period for Orchard. Since taking on the leadership, Frank and I, together with the executive team, have thought very carefully about what the new Orchard can become, how we can ensure that Orchard can fulfill its true potential and what we need to do to make that happen.

When we think about our strategic vision as a company, it's really all based on the potential of the hematopoietic stem cell gene therapy platform, where it can take us and the benefit it can provide for many patient populations even beyond our current portfolio of ultra-rare diseases. We have taken some bold and decisive actions that we believe will allow Orchard to achieve long-term growth and focus the company on sustainable value creation. This vision is supported by a new strategic plan that we have developed and which is built around four pillars. Each of these forms a chapter in our remarks this morning.

First, operating efficiencies. We have made a series of important changes to our operations that will enable us to sharpen our focus and more efficiently execute our strategy, which I will detail in a moment. Second is our commercial build. We are focused on establishing the right model for the diagnosis and treatment of patients undergoing HSC gene therapy, and see the true value of this approach over a series of ultra-rare products. Third, one of the most exciting areas in gene therapy right now is the innovation taking place in manufacturing technologies that have the potential to deliver economies of scale. We want to be leaders and invest in this space, knowing that our near-term capacity needs are covered by our experienced CDMO network.

Finally, central to this strategy is prioritizing our portfolio to enable the expansion of Orchard's pipeline beyond ultra-rare to less-rare indications. We are disclosing two new research programs for the first time today, and these are a genetic subset of frontotemporal dementia or FTD, and a genetic subset of Crohn's disease. We believe that the biological and clinical validation that has already been shown in our ultra-rare indications allow us to expand with confidence to these larger indications.

Turning to the first chapter in our new strategic plan. We are focused on improving the operational efficiency throughout the organization. This started with an extensive evaluation over the past six weeks of each program in our portfolio using several criteria that are shown here on the left-hand side of slide five. We undertook an objective analysis that involved both financial metrics and strategic considerations in identifying those programs where there was high need for patients and high-value creation for shareholders. As you can imagine, these were difficult decisions given the potentially transformative nature of many of these programs. Each has value, and we intend to realize that in different ways and over different time horizons.

Today, however, we believe our resources are best focused on Metachromatic Leukodystrophy, Wiskott-Aldrich syndrome, the MPS programs and our research programs. This also means that we have a balanced portfolio with late, mid and early stage programs. The programs I haven't mentioned such as OTL-101 and ADA-SCID and the transfusion-dependent, beta-thalassemia program, OTL-300, will have a reduced investment moving forward. We will look for alternative ways to realize value with those programs, including through partnerships.

So slide six brings together a summary of the operational changes that we've announced today. We believe these changes were important and necessary to enable Orchard to execute its mission and objectives at the highest level by matching our attention and resources to a set of core imperatives for the business. As summarized here, we expect to realize cash savings of approximately $15 million from the prioritization of our portfolio. Another $60 million in savings results from the decision to consolidate our R&D teams to one site and defer the investment in the manufacturing facility. Finally, the more staged approach to the commercial build-out and 25% reduction to our existing workforce and future headcount planning will each yield another $25 million in savings.

All of these cash savings are expected to be realized over 2020 and 2021, and result in total expected savings of $125 million over that period. With the revised plan, we now have cash runway into 2022 and no near term need to finance. It's worth briefly mentioning that this $125 million savings is after making investments in the following key areas to support our new strategy, shown on slide seven. In commercial, diagnostic and screening initiatives, including no-charge testing programs to help identify patients with MLD and other neurodegenerative conditions in time for treatment. In manufacturing, the technology, process innovations and efficiencies to drive scalability.

In R&D, initiatives in less-rare diseases that have the potential to fuel the company's future growth in a substantial way. This wasn't just an exercise to reduce expenses, but important decision-making to ensure our capital is deployed in a disciplined manner, while building a pipeline that can leverage our success across all phases of our business.

Now let me turn the call over to Frank to discuss additional key elements of the new plan.

Frank Thomas -- President and Chief Operating Officer

Thanks, Bobby, and good morning, everyone. As you can tell from this morning's press release, we have carefully examined each aspect of our business. You heard that a moment ago from Bobby, with the way we are creating operational efficiencies, and I think you will see additional evidence in the next two sections as we summarize our latest thinking around commercial deployment and manufacturing. Starting with commercial. We understand the importance of developing a commercial model that will demonstrate our ability to execute and bring these therapies to the market successfully. This model and the infrastructure that we build will also be leveraged for any future product launches.

As you'll note from the bottom of slide nine, each rare disease has certain dynamics that will impact the launch trajectory and speed with which we can penetrate the market. In fact, we anticipate our first two potential launches in WAS and MLD having distinct but complementary launch curves, as you can see from the illustrative diagrams. Let me start with MLD on the left, where we expect to launch first in the EU, followed by the U.S. and then other countries around the world. We think an important inflection point on the revenue curve with MLD will come later when newborn screening is established, providing an opportunity for an acceleration in growth rate. Disease progression is a second important dynamic that will affect market penetration. Because MLD advances so rapidly, it will be important to diagnose patients early and get them treated.

For Wiskott-Aldrich syndrome, the dynamics are very different, and it's reflected in the shape of the curve on the right. Unlike MLD, this disease is slower progressing and more readily diagnosed. We believe that WAS will provide an opportunity to treat a number of prevalent patients from the outset and also give us additional long-term revenue stream. This program, the BLA and MAA filings are on track for 2021. Turning back to MLD for an update on the regulatory time line. We are on track to get a decision from the European Medicines Agency later this year, and if approved, launch in the EU in the first half of 2021.

In the U.S., we recently engaged with the FDA on our planned BLA submission of OTL-200 for the treatment of MLD. The FDA has provided written feedback on the sufficiency of the company's data package, including the clinical endpoint, the natural history comparator and the CMC data package. As a result of this feedback, we intend to file an IND later this year and also seek RMAT designation, both of which we believe will facilitate a more comprehensive dialogue to discuss the data more fully and resolve the open matters before submitting a BLA. We are committed to working closely with the agency, and we'll provide updated guidance on the new filing time lines for the BLA after further regulatory interaction.

On slide 10, you can see that we're tracking nicely for the launch of OTL-200 in the EU in the first half of 2021, if approved, with Germany being the first country where we expect to treat commercial patients. Many of the prelaunch activities are under way, and the team has been able to keep up momentum during the pandemic to work with key centers and progress with site qualifications. We intend to set up a network of treatment centers where MLD patients are often referred and who also have transplant expertise. These same centers can be leveraged in future launches, especially for programs in the neurometabolic franchise.

I previously mentioned the importance of diagnosis in MLD to identify patients at early stages of disease, and we are taking the necessary steps to achieve long-term success. Beyond typical disease awareness efforts, we are also looking at initiatives such as no-charge diagnostic testing with partners such as Invitae, and we are looking to facilitate newborn screening for MLD with funding of upcoming pilots in New York State and Italy that are designed to validate the assay and provide the data for wider implementation. Success in these key initiatives will support early MLD patient identification.

Coming up quickly behind MLD and the neurometabolic franchise, our two proof-of-concept programs in MPS disorders, where we have made recent progress even during this challenging period with COVID-19. For MPS-I, over the past year, we've shown promising preliminary proof-of-concept data with positive engraftment, biomarker correction and encouraging early clinical outcomes, and we are excited to announce our plan to begin a registrational trial next year, bringing this program one step closer to commercialization.

For MPS-IIIA, we announced late last month that the first patient was treated in a proof-of-concept trial at Royal Manchester Children's Hospital, with enrollment planned to continue this year and interim data to be released in 2021. You can see graphically on slide 12 how the aggregation of these commercial markets lead to sustainable revenue growth. In addition, the infrastructure build is designed to provide the necessary commercial capabilities to realize the potential of the portfolio. On this slide, we've included the incidence figures for MLD and the incidence and prevalence figures for WAS to help you understand each opportunity as we see it today.

Given the dynamics at play for MLD that I described on slide nine, we believe this opportunity should largely be tied to the incident patient population, which we believe ranges from 200 to 600 patients per year in countries where rare diseases are often reimbursed. We've taken a more conservative view than previously on the addressable patient and market opportunity in countries such as those in the Middle East and Turkey, where the literature has a wide range of differing incident figures. Also, over time, with improved disease awareness, there may be prevalent patients identified who also could benefit from therapy. Our commercial strategy has always been and continues to be based not only on one product, but rather the aggregation of multiple potential products launching off one HSC gene therapy platform and infrastructure.

Turning to manufacturing. We've also made some key changes to our approach in manufacturing and how we allocate capital in the short and mid-term. On slide 14, you'll see the main tenets of our new manufacturing strategy. First, in the near term, we plan to focus on innovative technologies to enable commercial scalability.

Second, to ensure the appropriate focus on those technologies, we've made a decision to consolidate R&D to a single site in London, which brings together our organization in a more efficient way. This will allow efforts made to improve our manufacturing processes to be quickly and easily shared and then scaled commercially to transfer to our third party manufacturers, all of whom are currently located in Europe. As part of this consolidation, we will close our California site, including the termination of the Fremont project and associated capital spend.

Third, we have strong relationships with CDMOs that will ensure supply of clinical and commercial product to satisfy near-term requirements. And longer term, we intend to identify a new site in the U.S. to eventually bring manufacturing capabilities in-house with a facility that is appropriately sized and fitted for future techniques and operations.

Slide 15 shows the three phases of our approach in manufacturing: invest, partner and build. Today, we are investing, and we'll continue to invest in technologies such as transduction enhancers, stable producer cell line and closed automated processing of the drug product. This will potentially reduce the amount of vector needed, drive down COGS and potentially change the way products are manufactured, making it less labor-intensive, less expensive and more consistent. In the near and mid-term, we will continue to rely on our manufacturing partners for the early planned launches in MLD and WAS. For example, MolMed has been with these programs since the beginning, and they've been a reliable commercial partner with Strimvelis.

In addition to our existing CDMO network, we have begun to search for a drug product partner in the U.S. to complete a tech transfer and serve the U.S. market, thereby reducing scheduling challenges and creating some redundancy. And finally, over time, we plan to build in-house manufacturing capabilities closer to when there is a need for additional capacity. This enables us to explore options that are more aligned with our business in terms of scale and timing.

And with that, I'll turn the call back over to Bobby.

Bobby Gaspar, M.D., Ph.D. -- Chief Executive Officer

Thanks, Frank. In this section, I'm going to briefly highlight the potential of HSC gene therapy to correct not only blood lineage cells, but also how through natural mechanisms, specific cell types may allow correction of disease in specific organ systems and enable expansion of our portfolio into new research indications. As many of you know, and as shown on slide 17, through HSC gene therapy, we are able to insert a working copy of the gene permanently into the genome of HSCs, and these genetically modified cells can lead to multiple corrected cell types in the bloodstream, including immune cells, red blood cells and platelets.

In addition, HSCs can differentiate into cells of the monocyte macrophage lineage that naturally migrate into various organ systems, and thus gives us an opportunity to deliver genes and proteins directly to those organs, including the brain and the GI tract. Within the neurometabolic space, in particular, we have understood through our preclinical and clinical programs in MLD, MPS-I and MPS-IIIA how HSC gene therapy can deliver genes and proteins to the CNS to correct neurodegeneration. Here is an example of this natural mechanism at work in slide 18.

Data shows that there are a population of gene-modified HSCs that can naturally cross the blood-brain barrier, distribute throughout the brain, engraft as microglia and express enzyme that is taken up by neurons. We have seen this approach results in clinical benefits for patients with MLD, and we are also using the same approach for MPS-I and MPS-IIIA. Beyond this, we see that the HSC gene therapy approach could be used to deliver specific genes and proteins for other larger neurodegenerative conditions which have high unmet need.

One of the conditions we are disclosing today, and shown on slide 19, is a specific genetic subset of frontotemporal dementia, where the underlying pathogenesis has a number of parallels with the neurometabolic conditions that we are already addressing. This program involves a broad strategic alliance with Dr. Alessandra Biffi, Boston Children's Hospital and Padua University in Italy, to further explore the potential of ex vivo HSC gene therapy in neurometabolic and neurodegenerative conditions. In other organ systems, such as the GI tract, there are similar mechanisms at work which are illustrated on slide 20. Tissue resident macrophages in the gut wall are required to respond to bacterial invasion from the gut lumen and prevent infection. In certain disorders, such as X-linked chronic granulomatous disease or XCGD, defects in macrophage function results in an abnormal immune response and severe colitis.

Moving on to slide 21. We have already seen in our XCGD program the modification of HSCs and migration of gene-modified cells into the gut can lead to resolution of colitis through presumed reconstitution of the immune response. Certain subsets of Crohn's disease are also associated with mutations in genes that affect the response of macrophages to infection, and so our clinical observations that HSC gene therapy for XCGD suggest that the same approach may be applicable to this genetic subset of Crohn's disease. This preclinical work is ongoing in our Orchard research laboratories.

As we advance our work in FTD and Crohn's disease, and assuming we show preclinical proof-of-concept, these will become exciting opportunities for us to expand and address larger patient populations, either alone or in partnership. We believe we have truly just begun to explore the potential for HSC gene therapy in diseases such as these and others, and are excited to share more about the preclinical development of these programs later this year.

So to summarize our path forward on slide 22, the next 12 to 18 months offers many important milestones as we continue our evolution to a commercial stage company and advance our next wave of clinical stage therapies. We anticipate approval and launch of OTL-200 for MLD in the EU, additional regulatory filings in Wiskott-Aldrich syndrome and MLD, a new registrational study next year in MPS-I, multiple clinical data readouts from our neurometabolic franchise and further detail and progress on our research programs in FTD and Crohn's disease.

To wrap up our prepared remarks, we are confident that our new strategic plan and operational decisions announced today will set us on the right path to achieve long-term growth, build sustainable value and serve an even larger number of patients who could benefit from hematopoietic stem cell gene therapy.

Thank you very much. And now we'll use the rest of the time to answer your questions. So let's have the operator open up the line.

Operator

Thank you. [Operator Instructions] And our first question comes from Whitney Ijem from Guggenheim. Your line is now open. Please go ahead.

Whitney Ijem -- Guggenheim -- Analyst

Hey guys, thanks for the question. So first, just wondering, can you give us some more color maybe on the discussions you're having with the FDA in MLD? Kind of what are they looking for? And I guess is the IND just sort of a tool to get RMAT? Or is there additional kind of clinical work you plan you think you'll need to do?

Bobby Gaspar, M.D., Ph.D. -- Chief Executive Officer

Hi. Whitney, Bobby here. Thanks for that. In general, we can't go into all of the details, obviously, of the discussions with the FDA. But I think in the release and in the script, we've talked about the fact that they've commented on certain endpoints, the natural history, the CMC package, etc. Now I think I'd just like to say this is a and obviously, a very complex disease, a very ultra-rare population, we have extensive data set, and we have already filed with the EMA. Now for historical reasons, there hasn't been an IND in the U.S., and so we haven't had the opportunity to discuss that data in full with the FDA.

What I can say is that we do have an extensive body of data. We want to be able to talk to the FDA and have a comprehensive dialogue to be able to explain that full data set. We feel confident that we have the endpoints that they are looking for and the data that they are asking for. But we need to have that conversation with them in order to be explain to be able to do that fully. So that's why we're filing an IND filing, filing the RMAT, so we can have that dialogue. And once we can clarify those issues, then we can go ahead with submission of the BLA.

Whitney Ijem -- Guggenheim -- Analyst

Okay. Got it. And then just one quick follow-up on MLD. Can you remind us where you are with newborn screening, I guess, both in Europe and then in the U.S.?

Bobby Gaspar, M.D., Ph.D. -- Chief Executive Officer

Yes, sure. So newborn screening for MLD, I think, is an important, a very important issue, because, obviously, that means that we'll be able to get earlier diagnosis and have more patients be able to access therapy. So it's a very important part of our kind of diagnostic initiatives in this disease. What we have so far is that we have worked with a key scientist, where an assay has been developed, that's been published to show that there is an assay that we've done on a dry blood spot to understand the decrease in the enzyme activity and also the increase in the sulfur-type levels.

And that assay is now going to be put into pilots, and we are funding a pilot in New York State, and that will start later this year. And we're also looking at pilots in other states as well. We're also transferring that assay to Italy and that and we're funding a program in Tuscany and in Italy where that will be rolled out. And we're also looking for opportunities in other EU states as well. So I'd say, there are already two that are going to start, we are looking to fund other pilots as well.

And together, that data will allow us to validate the assay but also allow wider implementation of newborn screening, and also for nomination, for example, onto the WAS panel for implementation in states in the U.S. So I say there's a lot of work going on in order to make sure that happens.

Whitney Ijem -- Guggenheim -- Analyst

Great, thanks.

Bobby Gaspar, M.D., Ph.D. -- Chief Executive Officer

Thank you.

Operator

And your next question comes from Esther Rajavelu from Oppenheimer. Your line is now open. Please go ahead.

Esther Rajavelu -- Oppenheimer -- Analyst

Hey guys. Congrats on all the changes. I guess, my first question again on MLD is I'm trying to understand the duration between EU approval and NBS. I don't know if that math or if that graph was drawn to scale, but it looks like it's almost a four-year lag from first approval to newborn screening. Can you help us understand the time line there?

Frank Thomas -- President and Chief Operating Officer

You mean between EU and U.S. or around newborn screening or both?

Esther Rajavelu -- Oppenheimer -- Analyst

Around newborn screening, generally, between EU approval and newborn screening.

Frank Thomas -- President and Chief Operating Officer

Yes, sure. As Bobby mentioned, there's a pretty active program planned around newborn screening that I think we will expect will come over time in order to even apply for the Ross Panel, there are certain requirements that need to be met in terms of the number of patients or a number of children that have to be screened, identifying the positive patients and then you can apply on the Ross Panel. And then from there, there's a process that you go through in the U.S., at least, on a state-by-state basis to get it added.

So I think there are a number of steps along the way. We haven't guided specifically on the time line, but I think there are other precedents out there that suggest that this could take years. Once we screen the once we apply for the Ross Panel to get sort of full reimbursement, but obviously, we'll focus on states initially after that approval that have the largest populations.

Esther Rajavelu -- Oppenheimer -- Analyst

And my Yes, go ahead.

Bobby Gaspar, M.D., Ph.D. -- Chief Executive Officer

Esther for I was just going to say for the EU, obviously, we're looking for approval for MLD later this year. As far as people screening in the EU is concerned, that's on a country-by-country basis, and sometimes it's even certain states. But I've worked on newborn screening for SCID, for example, in the EU. And now there are numerous countries in the EU that are screening for SCID with a number of pilots also in the pipeline as well. And so with that kind of experience, and we would be looking to kind of really facilitate that uptake in the EU and as in and in the U.S., as Frank has already mentioned.

Esther Rajavelu -- Oppenheimer -- Analyst

Understood. And then the decision to defer capex, is that related to some of the time lines for U.S. versus EU approvals and the newborn screening? Or what really kind of went into that delay, given you already have some cost into that facility?

Frank Thomas -- President and Chief Operating Officer

Yes. I can start, and Bobby can add on that again. I think, obviously, we continue to believe in-house manufacturing is an important capability that we're going to want to have over some period of time. It really comes down to sort of when is the need for that capacity and capability relative to the various programs we have. Working with the CDMOs that we have today, we know that we have capacity for the MLD and WAS launches and for a period beyond the launch. So there's not an imminent need to secure the capacity today, and we think that deferring it makes the most sense. We'll continue to work with CDMOs on those launches.

We will look at bringing on a U.S. supplier for drug product to be able to more easily service the U.S. market. And then longer term, look at, potentially, in-house manufacturing at a site and location that we think is more fitted to what the capacity needs will be. So I wouldn't say it's tied to any sort of launch time lines because the plan always was to utilize CDMOs for WAS and MLD. But certainly, as those launches roll out and demand grows, our capacity needs will grow and that will be the appropriate time, we think, to make the investment.

Esther Rajavelu -- Oppenheimer -- Analyst

Understood. Thank you very much.

Bobby Gaspar, M.D., Ph.D. -- Chief Executive Officer

Thank you.

Operator

And your next question comes from Anupam Rama from JPMorgan. Your line is now open. Please go ahead.

Tessa Romero -- JPMorgan -- Analyst

Good morning, guys. This is Tessa on the call this morning for Anupam. You pointed out that updated interim data from the proof-of-concept trial for OTL-203 and MPS-I is expected at ASGCT upcoming here next week. Can you remind us of what will be the size and scope of data that we will see at the conference? And maybe can you just clarify if there is any other newly updated clinical data we should be thinking about for other programs at ASGCT?

Bobby Gaspar, M.D., Ph.D. -- Chief Executive Officer

Okay, fine. Bobby here, and I'll take this question. On MPS-I, so just to remind you, the proof-of-concept study has enrolled all eight patients, so that's been fully recruited into. What we've shared with you previously is biochemical data showing the overexpression of IDUA activity, the decrease in the heparan and dermatan sulfate, the engraftment of gene-modified cells and some early clinical data on patients who have got beyond the one-year time frame after gene therapy. There was only previously one patient who had reached that time point.

So there's been further follow-up on those eight patients. We'll be able to show you longer-term engraftment of the gene-modified cells, more consistent overexpression of enzymatic activity, longer follow-up, decrease in GAG levels and also more clinical data on patients who have got to longer endpoints as well. So we'll be able to show data assay on clinical data on patients after longer follow-up. And this will be both on their cognitive outcome, but we also will have data on, for example, growth parameters as well, which is again a big issue in MPS-I. So that is for MPS-I.

We will also be sharing data on OTL-101 as well for ADA-SCID. There will be further follow-up on patients who have undergone treatment for transfusion-dependent beta-thalassemia, so longer follow-up on the patients who have been treated so far. So there's really quite, as well as other programs. So there's really quite an extensive body of data, and it just showcases the potential of Orchard's platform across a number of different diseases and how HSC gene therapy can correct the underlying defects in immune deficiencies, neurometabolic deficiencies and hemoglobin opportunities as well. And obviously, we'll give you more detail on those different abstracts next week.

Tessa Romero -- JPMorgan -- Analyst

Great, thank you.

Bobby Gaspar, M.D., Ph.D. -- Chief Executive Officer

Thank you.

Operator

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Orchard Therapeutics (ORTX) Q1 2020 Earnings Call Transcript - Motley Fool

Pratteln, Switzerland, May06, 2020 Santhera Pharmaceuticals (SIX: SANN) announces the signing of two agreements with Rutgers, The State University of New Jersey as part of its program to advance gene therapy research for the treatment of LAMA2-deficient congenital muscular dystrophy (LAMA2MD or MDC1A). Under the agreements, Santhera gains rights to intellectual property developed at Rutgers on certain gene constructs that will be further studied under a collaboration agreement.

Santhera has entered into a license agreement with Rutgers, The State University of New Jersey and a collaboration with Prof. Peter Yurchenco, a pioneer in a novel gene therapy approach for the treatment of LAMA2MD. These agreements complement the ongoing collaboration of Santhera with Prof. Markus Regg from the Biozentrum of the University of Basel [1]. Previous collaborative work by Prof. Regg and Prof. Yurchenco has established the potential of this approach in animal models.

The novel gene therapy strategy developed by these leading experts uses two linker proteins that are composed of domains derived from extracellular matrix proteins agrin, laminin and nidogen [2-5]. In animal models for LAMA2MD, this approach has led to restoration of muscle fiber basement membranes, recovery of muscle force and size, increased overall body weight and markedly prolonged survival thus demonstrating strong evidence for disease modifying potential [2].

The coordinated work of both collaborations will further advance Santheras effort to bring this innovative gene therapy approach to patients with LAMA2MD.

Gene replacement is a promising therapeutic option for the treatment of LAMA2MD, said Peter D. Yurchenco, MD, PhD, Professor at Rutgers Robert Wood Johnson Medical School, USA. We have been working on continuously optimizing linker proteins engineered from extracellular matrix proteins which will aid in advancing such gene therapy approach towards clinical use.

Santhera is excited to extend its collaborative network for this therapeutic approach, now including experts from Rutgers University, added Kristina Sjblom Nygren, MD, Chief Medical Officer and Head of Development of Santhera. This will add value to our gene therapy program for LAMA2MD and complements the work already under way with the Biozentrum at the University of Basel, which was awarded a grant by Innosuisse in 2019. Both of our collaboration partners have pioneered this field and will work closely with Santhera, clinical experts and the patient community to establish the best way to bring this approach to clinical use.

About LAMA2MD (CMD Type 1A or MDC1A) and Emerging Therapy ApproachesCongenital muscular dystrophies (CMDs) are inherited neuromuscular diseases characterized by early-onset weakness and hypotonia alongside associated dystrophic findings in muscle biopsy. Progressive muscle weakness, joint contractures and respiratory insufficiency characterize most CMDs. Laminins are proteins of the extracellular matrix that help maintain muscle fiber stability by binding to other proteins. LAMA2-related muscular dystrophy (LAMA2MD, also called MDC1A), is one of the most common forms of CMD. It is caused by mutations in the LAMA2 gene encoding the alpha2 subunit of laminin-211. Most LAMA2MD patients show complete absence of laminin-alpha 2, are hypotonic (floppy) at birth, fail to ambulate, and succumb to respiratory complications.

Previous work has demonstrated that two linker proteins, engineered with domains derived from the extracellular matrix proteins agrin, laminin and nidogen, could compensate for the lack of laminin-alpha2 and restore the muscle basement membrane [2-5]. Through simultaneous expression of artificial linkers (SEAL), this gene therapy approach aims to overcome the genetic defect by substituting laminin-alpha2 deficiency with small linker proteins containing necessary binding domains to re-establish muscle fiber integrity. In a transgenic mouse model, the linker expression increased the lifespan of LAMA2-deficient mice 5-fold to a median of 81 weeks compared to 15.5 weeks in the disease model without the therapeutic linker expression [2]. Recently, it was demonstrated that such linker constructs could be applied by standard adeno-associated virus (AAV) vectors [6, 7]. First results using the AAV technology have been presented by Prof Regg [8].

References [1] Santhera press release on gene collaboration with Biozentrum Basel (May 21, 2019), accessible here

[2] Reinhard et al. (2017). Sci Transl Med 9, eaal4649[3] Moll et al. (2001). Nature 413, 302-307.

[4] Meinen et al. (2007) J. Cell Biol. 176, 979-993.[5] McKee et al. (2017) J. Clin. Invest. 127, 1075-1089.[6] Qiao et al. (2018) Mol Ther Methods Clin Dev 9, 47-56.

[7] Qiao et al. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 11999-12004.[8] Reinhard, J. et al. (2019) Neuromuscular Disorders, Volume 29, S164

About Rutgers, The State University of New JerseyRutgers, The State University of New Jersey, is a leading national research university and the state of New Jerseys preeminent, comprehensive public institution of higher education. Established in 1766, the university is the eighth-oldest higher education institution in the United States. More than 71,000 students and 23,000 faculty and staff learn, work and serve the public at Rutgers University-New Brunswick, Rutgers University-Newark, Rutgers University-Camden, and Rutgers Biomedical and Health Sciences.

About Santhera Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative medicines for rare neuromuscular and pulmonary diseases with high unmet medical need. Santhera is building a Duchenne muscular dystrophy (DMD) product portfolio to treat patients irrespective of causative mutations, disease stage or age. A marketing authorization application for Puldysa (idebenone) is currently under review by the European Medicines Agency. Santhera has an option to license vamorolone, a first-in-class anti-inflammatory drug candidate with novel mode of action, currently investigated in a pivotal study in patients with DMD to replace standard corticosteroids. The clinical stage pipeline also includes lonodelestat (POL6014) to treat cystic fibrosis (CF) and other neutrophilic pulmonary diseases, as well as omigapil and an exploratory gene therapy approach targeting congenital muscular dystrophies. Santhera out-licensed ex-North American rights to its first approved product, Raxone (idebenone), for the treatment of Leber's hereditary optic neuropathy (LHON) to Chiesi Group. For further information, please visit http://www.santhera.com.

Raxone and Puldysa are trademarks of Santhera Pharmaceuticals.

For further information please contact: public-relations@santhera.com orEva Kalias, Head External CommunicationsPhone: +41 79 875 27 80eva.kalias@santhera.com

Disclaimer / Forward-looking statements This communication does not constitute an offer or invitation to subscribe for or purchase any securities of Santhera Pharmaceuticals Holding AG. This publication may contain certain forward-looking statements concerning the Company and its business. Such statements involve certain risks, uncertainties and other factors which could cause the actual results, financial condition, performance or achievements of the Company to be materially different from those expressed or implied by such statements. Readers should therefore not place undue reliance on these statements, particularly not in connection with any contract or investment decision. The Company disclaims any obligation to update these forward-looking statements.# # #

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Santhera Signs Agreements in Gene Therapy Research for Congenital Muscular Dystrophy with Rutgers University - GlobeNewswire

For Immediate Release: May 08, 2020

Today, the U.S. Food and Drug Administration approved Retevmo (selpercatinib) capsules to treat three types of tumors non-small cell lung cancer, medullary thyroid cancer and other types of thyroid cancers in patients whose tumors have an alteration (mutation or fusion) in a specific gene (RET or rearranged during transfection). Retevmo is the first therapy approved specifically for cancer patients with the RET gene alterations.

Innovations in gene-specific therapies continue to advance the practice of medicine at a rapid pace and offer options to patients who previously had few, said Richard Pazdur, M.D., director of the FDAs Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDAs Center for Drug Evaluation and Research. The FDA is committed to reviewing treatments like Retevmo that are targeted to specific subsets of patients with cancer.

Specifically, the cancers that Retevmo is approved to treat include:

Retevmo is a kinase inhibitor, meaning it blocks a type of enzyme (kinase) and helps prevent the cancer cells from growing. Before beginning treatment, the identification of a RET gene alteration must be determined using laboratory testing.

The FDA approved Retevmo on the results of a clinical trial involving patients with each of the three types of tumors. During the clinical trial, patients received 160 mg Retevmo orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR), which reflects the percentage of patients that had a certain amount of tumor shrinkage, and duration of response (DOR).

Efficacy for NSCLC was evaluated in 105 adult patients with RET fusion-positive NSCLC who were previously treated with platinum chemotherapy. The ORR for the 105 patients was 64%. For 81% of patients who had a response to the treatment, their response lasted at least six months. Efficacy was also evaluated in 39 patients with RET fusion-positive NSCLC who had never undergone treatment. The ORR for these patients was 84%. For 58% of patients who had a response to the treatment, their response lasted at least six months.

Efficacy for MTC in adults and pediatric patients was evaluated in those 12 years of age and older with RET-mutant MTC. The study enrolled 143 patients with advanced or metastatic RET-mutant MTC who had been previously treated with cabozantinib, vandetanib or both (types of chemotherapy), and patients with advanced or metastatic RET-mutant MTC who had not received prior treatment with cabozantinib or vandetanib. The ORR for the 55 previously treated patients was 69%. For 76% of patients who had a response to the treatment, their response lasted at least six months. Efficacy was also evaluated in 88 patients who had not been previously treated with an approved therapy for MTC. The ORR for these patients was 73%. For 61% of patients who had a response to the treatment, their response lasted at least six months.

Efficacy for RET fusion-positive thyroid cancer was evaluated in adults and pediatric patients 12 years of age and older. The study enrolled 19 patients with RET fusion-positive thyroid cancer who were radioactive iodine-refractory (RAI, if an appropriate treatment option) and had received another prior systemic treatment, and eight patients with RET fusion-positive thyroid cancer who were RAI-refractory and had not received any additional therapy. The ORR for the 19 previously treated patients was 79%. For 87% of patients who had a response to the treatment, their response lasted at least six months. Efficacy was also evaluated in eight patients who had not received therapy other than RAI. The ORR for these patients was 100%. For 75% of patients who had a response to the treatment, their response lasted at least six months.

The most common side effects with Retevmo were increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes in the liver, increased blood sugar, decreased white blood cell count, decreased albumin in the blood, decreased calcium in the blood, dry mouth, diarrhea, increased creatinine (which can measure kidney function), increased alkaline phosphatase (an enzyme found in the liver and bones), hypertension, fatigue, swelling in the body or limbs, low blood platelet count, increased cholesterol, rash, constipation and decreased sodium in the blood.

Retevmo can cause serious side effects including hepatotoxicity (liver damage or injury), elevated blood pressure, QT prolongation (the heart muscle takes longer than normal to recharge between beats), bleeding and allergic reactions. If a patient experiences hepatotoxicity, Retevmo should be withheld, dose reduced or permanently discontinued. Patients undergoing surgery should tell their doctor as drugs similar to Retevmo have caused problems with wound healing.

Retevmo may cause harm to a developing fetus or a newborn baby. Health care professionals should advise pregnant women of this risk and should advise both females of reproductive potential and males patients with female partners of reproductive potential to use effective contraception during treatment with Retevmo and for one week after the last dose. Additionally, women should not breastfeed while on Retevmo.

Retevmo was approved under the Accelerated Approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally provide a meaningful advantage over existing treatments. The FDA also granted this application Priority Review and Breakthrough Therapy designation, which expedites the development and review of drugs that are intended to treat a serious condition, when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies. Additionally, Retevmo received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Retevmo to Loxo Oncology, Inc., a subsidiary of Eli Lilly and Company.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nations food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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FDA Approves First Therapy for Patients with Lung and Thyroid Cancers with a Certain Genetic Mutation or Fusion - FDA.gov

It works like a very fine "molecular knob" able to modulate the electrical activity of the neurons of our cerebral cortex, crucial to the functioning of our brain. Its name is Foxg1, it is a gene, and its unprecedented role is the protagonist of the discovery just published on the journal Cerebral Cortex. Foxg1 was already known for being a "master gene" able to coordinate the action of hundreds of other genes necessary for the development of our anterior central nervous system. As this new study reports, the "excitability" of neurons, namely their ability to respond to stimuli, communicating between each other and carrying out all their tasks, also depends on this gene. To discover this, the researchers developed and studied animal and cellular models in which Foxg1 has an artificially altered activity: a lack of activity, as it happens in patients affected by a rare variant of Rett Syndrome, which leads to clinical manifestations of the autistic realm; or an excessive action, as in a specific variant of the West Syndrome, with neurological symptoms such as serious epilepsy and severe cognitive impairment. As deduced by the scientists in the research, the flaw in the "knob" lies in an altered electrical activity in the brain with important consequences for the entire system, similar to what happens in the two syndromes mentioned.

Shedding light on this mechanism, say the researchers, allows to understand more deeply the functioning of our central nervous system in sickness and in health, a fundamental step to assess possible future therapeutic interventions for these pathologies. What has just been published is the latest in a series of three studies on the Foxg1 gene, recently published by the researchers of SISSA on Cerebral Cortex. It is the result of a project begun more than five years ago, which saw the team of Professor Antonello Mallamaci of SISSA in the front line with researchers of the University of Trento and the Neuroscience Institute of Pisa, with the support of the Telethon Foundation, of the Fondation Jerome Lejeune and of the FOXG1 Research Foundation.

The many abilities of the "master gene"

"We knew that this gene is important for the development of the anterior central nervous system" explains the Professor Antonello Mallamaci of SISSA, who has coordinated the research. "In previous studies we had already highlighted how it was involved in the development of particular brain cells, the astrocytes, as well as the neuronal dendrites, which are part of the nerve cells that transport the incoming electrical signal to the cell. The fact that it had mutated in patients affected by specific variants of the Rett and West Syndromes in which we see, respectively, an insufficient and excessive activity of this gene, made us explore the possibility that its role was also another. And, from what has emerged, it would appear that way".

The research findings

According to the study, the activation of the electrical activity of Foxg1 follows a positive circuit. Professor Mallamaci explains: "If the gene is very active there is increased electrical activity in the cerebral cortex. In addition, the neurons, when active, tend to make it work even harder. One process, in short, feeds the other. Obviously, in normal conditions, the system is slowed down at a certain point. "If, however, the gene functions abnormally, or it is found in a number of copies other than two, as it happens in the two syndromes above, the point of balance changes and the electrical activity is altered. All this, in addition to making us understand the mechanisms of the pathology, tells us that Foxg1 functions precisely as a key regulator of the electrical activity in the cerebral cortex".

The next step, explains the professor, will be to understand the role of the mediating genes, namely of some of the many genes whose action is regulated by the master gene Foxg1. This analysis is important to understand in more detail how this gene works under normal and pathological conditions.

How the master gene produces the pathological effects, when and how to intervene

Understanding the molecular mechanisms that Foxg1 controls is also important to study what could be the targets on which to intervene for possible therapeutic approaches. "Given that finding a therapy for these illnesses is very difficult, working so in depth you might find, for example, that most problems are caused precisely by some of the "operators" that Foxg1 regulates. And that we should therefore focus our attention on these goals, rather than on the master gene, maybe using drugs that already exist and have been seen to be useful in remedying those specific flaws". In the case of a future approach that would instead correct the anomalies of the FOXG1 gene with the gene therapy, explains Professor Mallamaci, "it is necessary to understand when to intervene, namely from what moment on the pathological effects due to the mutation of this gene become irreversible. To replace the flawed copy with the correct one, it is necessary to intervene before that moment, which might suppose you would have to make a prenatal gene diagnosis and treatment". "The next steps we will take", concludes Professor Mallamaci "will be directed precisely in the direction of a deeper understanding of all these aspects".

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Like a molecular knob: That is how a gene controls the electrical activity of the brain - Science Codex