Archive for the ‘Gene Therapy Research’ Category

]]> The company signed gene therapy deals with Novartis and Sarepta Therapeutics. Credit: Gerd Altmann from Pixabay.

Biotechnology company Dyno Therapeutics has launched from stealth mode with focus on using artificial intelligence (AI) technology to develop adeno-Associated Virus (AAV) vectors.

The company signed gene therapy deals with Novartis and Sarepta Therapeutics.

Dyno Therapeutics and Novartis will create improved AAV vectors for research, development and commercialisation of gene therapies across ocular diseases.

The partnership will leverage Dynos CapsidMap AI platform in combination with Novartis gene therapy development and global commercialisation expertise.

Dyno will use AI technology and its suite of machine learning and experimental tools to design and identify AAV capsids with improved functional properties for gene therapy.

Later, Novartis will carry out preclinical, clinical and commercialisation activities for the gene therapy candidates developed using the AAV capsids.

Dyno will gain upfront consideration, research funding, licence fees, along with potential clinical, regulatory and sales milestone payments.

Dyno Therapeutics CEO and cofounder Eric Kelsic said: With their extensive ophthalmologic expertise, Novartis is an ideal partner to leverage Dynos platform to design AI-powered vectors to expand the impact of gene therapies for ocular diseases.

This collaboration is a major step forward in our plan to realise the potential of Dynos CapsidMap platform for gene therapies to improve patient health.

Meanwhile, the company will work with Sarepta Therapeutics to use its CapsidMap platform to develop next-generation AAV vectors for muscle diseases.

Under the deal, Dyno will design and discover AAV capsids for gene therapy while Sarepta will conduct preclinical, clinical and commercialisation for product candidates resulting from the alliance.

Dyno could get more than $40m in upfront, option and licence payments during the research phase. Also, if Sarepta develops and commercialises product candidates for various muscle diseases, Dyno will receive milestone payments.

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Dyno Therapeutics launches with deals from Novartis and Sarepta - Pharmaceutical Technology

Repeated setbacks aside, little Capricor has suggested it has generated some long-term data to support its pursuit to garner approval for its stem cell therapy for Duchenne muscular dystrophy, although some of the data appeared to underwhelmed investors.

The data from the small, placebo-controlled mid-stage study, HOPE-2, tracked the effects of the companys stem cell therapy CAP-1002, which is designed to temper the inflammation associated with DMD, in 8 boys and young men who are in advanced stages of DMD. The remaining 12 enrolled patients received the placebo.

The main goal of the study was a measure that evaluates shoulder, arm and hand strength in patients who are generally non-ambulant (performance of the upper limb (PUL) 2.0), as suggested by the FDA, Capricor said. It is one of several ways Capricor quantified skeletal muscle improvement in the trial.

The intravenous infusion of CAP-1002, given every 3 months, induced a statistically meaningful improvement of 2.4 points (p=0.05) versus the placebo group, in which patient declines were consistent with natural history data. However, on another measure of upper limb function, the trend was in favor of the Capricor drug, but did not hit statistical significance.

The companys shares $CAPR were down nearly 13% to $6.89 in morning trading.

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Meanwhile, there were also some encouraging data on cardiac function the genetic condition is characterized by progressive weakness and chronic inflammation of the skeletal, heart and respiratory muscles.

As reflected above, CAP-1002 elicited an improvement across different measures of cardiac function, although the effect was not always statistically significant. In particular, the drug also caused a reduction in the levels of the biomarker CK-MB, an enzyme that is only released when there is cardiac muscle cell damage.

Armed with these data and an RMAT and orphan drug designation from the FDA, Capricor is now hoping to eke out a plan with the FDA for marketing approval.

LA-based Capricor initially set out to test the potential of technology that Eduardo Marbn, CEO Linda Marbns husband, developed at Johns Hopkins. But repeated setbacks clobbered the company, which in 2014 traded north of $14 a share. In 2017, J&J walked away from a collaboration on a stem cell therapy for damaged hearts after it flopped in the clinic.

In late 2018, the company voluntarily halted a DMD clinical trial, following a severe allergic reaction that occurred during infusion. In February 2019, the company said it is exploring strategic alternatives for one or more of its products and cutting 21 jobs to keep financially afloat, but had resumed dosing in its DMD trial.

The first batch of positive data on CAP-1002, which consists of progenitor cells derived from donor hearts and is designed to exude exosomes that initiate muscle repair by suppressing inflammation and driving immunomodulation, came last July when the company announced the drug had generated a positive effect at the interim analysis juncture of HOPE-2. Capricor is now working on to flexing its therapeutic muscle with CAP-1002 to fight the Covid-19 pandemic.

DMD is a rare muscle-wasting disease caused by the absence of dystrophin, a protein that helps keep muscle cells intact. It disproportionately affects boys and affects roughly 6,000 in the United States.

Patients are essentially treated with steroids. Sarepta Therapeutics now has two exon-skipping drugs designed to treat certain subsets of the disease, although the magnitude of their effect is controversial given that approvals were not based on placebo-controlled data. Meanwhile, Sarepta and others are also pursuing one-time cures in the form of gene therapies to replace the missing dystrophin gene in patients.

Social: Linda Marbn, Capricor CEO (Twitter)

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One year on, Capricor's stem cell therapy appears to help DMD patients in small study, but investors balk at the data - Endpoints News

Global Gene Therapy for Age-related Macular Degeneration Market research report provides detail information about Market Introduction, Market Summary, Global market Revenue (Revenue USD), Market Drivers, Market Restraints, Market Opportunities, Competitive Analysis, Regional and Country Level.

Gene Therapy for Age-related Macular Degeneration Market Size Covers Global Industry Analysis, Size, Share, CAGR, Trends, Forecast And Business Opportunity.

>>Need a PDF of the global market report? Visit: https://industrystatsreport.com/Request/Sample?ResearchPostId=11998&RequestType=Sample

Latest research report on Gene Therapy for Age-related Macular Degeneration Market delivers a comprehensive study on current market trends. The outcome also includes revenue forecasts, statistics, market valuations which illustrates its growth trends and competitive landscape as well as the key players in the business.

Macular degeneration is a condition in which, macula, a part of the retina, gets damaged or deteriorated. This condition usually affects individuals who are aged 50 years and above and therefore, it is called age-related macular degeneration (AMD). AMD is the leading cause of vision loss and is directly related to the advancement of age. But smoking also plays a vital role in causing AMD. AMD is characterized by the presence of a blurred area near the center of vision that leads to distorted vision. There are two different types of AMD, including dry (atrophic) AMD (dAMD) and wet (neovascular/exudative) AMD (wAMD). The dAMD is the most common type of AMD and accounts for almost 80%-90% of the overall AMD cases.

It has been observed that age-related macular degeneration (AMD) is one of the major causes for vision loss and is characterized by the formation of a blurred area near the center of vision, a condition that mostly affects the geriatric population. According to the CDC, almost 2 million individuals in the US suffer from AMD and by 2050, this number will reach more than 5 million. This will subsequently demand the need for the development of innovative treatments for AMD, driving the markets growth.

The market research analysts have predicted that with the introduction of techniques such as fluorescein angiography, the global age-related macular degeneration market will register a CAGR of more than 7% by 2020. With the unavailability of FDA-approved treatment for dry AMD (dAMD) and the treatment of wet AMD (wAMD) involving the need of intravitreal injections for an indefinite period, gene therapy is emerging as the most-efficient approach for the treatment of age-related macular degeneration (AMD).

According to this pipeline analysis report, most of the gene therapy molecules in the pipeline are being developed for wet AMD (wAMD). Our market research analysts have also identified that most of these molecules are in the pre-clinical development stage and a considerable number of molecules have been discontinued from development.

This report focuses on the global Gene Therapy for Age-related Macular Degeneration status, future forecast, growth opportunity, key market and key players. The study objectives are to present the Gene Therapy for Age-related Macular Degeneration development in United States, Europe and China.

The key players covered in this study RetroSense Therapeutics REGENXBIO AGTC

Market segment by Type, the product can be split into Subretinal Intravitreal Unspecified

Market segment by Application, split into Monotherapy Combination Therapy

In this study, the years considered to estimate the market size of Gene Therapy for Age-related Macular Degeneration are as follows: History Year: 2014-2018 Base Year: 2018 Estimated Year: 2019 Forecast Year 2019 to 2025

Market segment by Regions/Countries, this report covers United States Europe China Japan Southeast Asia India Central & South America

The study objectives of this report are: To analyze global Gene Therapy for Age-related Macular Degeneration status, future forecast, growth opportunity, key market and key players. To present the Gene Therapy for Age-related Macular Degeneration development in United States, Europe and China. To strategically profile the key players and comprehensively analyze their development plan and strategies. To define, describe and forecast the market by product type, market and key regions.

For the data information by region, company, type and application, 2018 is considered as the base year. Whenever data information was unavailable for the base year, the prior year has been considered.

Need a PDF of the global market report? Visit: https://industrystatsreport.com/Request/Sample?ResearchPostId=11998&RequestType=Methodology

Table of Content:

Market Overview: The report begins with this section where product overview and highlights of product and application segments of the Global Gene Therapy for Age-related Macular Degeneration 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 Gene Therapy for Age-related Macular Degeneration 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 Gene Therapy for Age-related Macular Degeneration 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 Gene Therapy for Age-related Macular Degeneration 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 Gene Therapy for Age-related Macular Degeneration 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 Gene Therapy for Age-related Macular Degeneration Market.

Market Forecast: Here, the report offers a complete forecast of the Global Gene Therapy for Age-related Macular Degeneration 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.

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Covid 19 Pandemic: Gene Therapy for Age-related Macular Degeneration Market Size is Thriving Worldwide- Demand and Analysis 2019-2025 - Cole of Duty

Doctors in Southern California are working with researchers in Arizona to better understand the bodys sometimes bizarre immune response to COVID-19 an antibody onslaught that may kill the patient, rather than kill the virus.

The nonprofit Translational Genomics Research Institute (TGen), an affiliate of City of Hope, is peering into specific proteins on the virus to see how they react with different antibodies a high-resolution view that might guide treatment, testing and vaccine development.

The hypothesis is that antibodies can make things worse, and thats whats killing some people, said John Altin, assistant professor in TGens infectious-disease branch. We want to understand how that might be different from an immune response that protects somebody.

As many critically ill patients are treated in clinical trials with convalescent plasma therapy that is, injecting antibodies from recovered COVID-19 patients into those who are very ill, in hopes of triggering protective immune responses its imperative to understand whats behind the differing reactions.

Usually, antibodies provide protection, but there may be a bit of an exception with this virus, Altin said. That is a serious concern.

To that end, TGen and the Center for Gene Therapy at City of Hope are cooperating on a COVID Immunity Study that aims to collect blood from COVID-19 survivors.

The researchers will analyze your blood and profile your immune memory, the study consent form explains.

Participants can use the TGen kit at home. Theyll get a study kit by mail and collect one small spot blood sample, via a finger-prick device, for two consecutive weeks. Then theyll mail the study kit back to TGen.

About 500 people are expected to participate through the course of the study, and researchers may reach out for additional samples, and/or with additional questions, to see how immune memory changes over time.

Participants must be U.S. residents, at least 18 years old, have tested positive for COVID-19, and then recovered. For more information, see https://covidimmunity.org/.

This will help us learn more about how, when and why we produce antibodies in response to a COVID-19 infection, said David Engelthaler, director of TGen North, in a prepared statement. One class of antibodies tackles the infection first, and then another comes in to finish the job. Knowing when these different immune responses occur, and how long they last, could help us understand if some patients gain a certain degree of immunity against reinfection. We need to know how that works.

While large-scale clinical trials involving convalescent plasma are under way all over the nation, this study aims not to treat the disease, but to better understand the mechanisms behind it.

TGen describes its approach as a high-resolution view of the antibody response. It seeks to not only map the viruss proteins in detail, but to also see which parts of those proteins are targeted by antibodies.

Our approach will not only tell you which proteins arebeing targeted, but also be able to tell which regions of each protein are being targeted, Altin said in a statement. Each protein can be recognized by many different types of antibodies. By looking at this level of detail, we then could see elements of the antibody response that others might be missing.

TGen hopes to tease out subtle differences that can help develop therapies, vaccines and better antibody testing.

Others are looking at responses to the entire protein. Our approach is a little different. When we look at the antibody response, we divide it up into thousands of pieces. Theres potential for that to tell us what a beneficial and un-beneficial response might look like, Altin said.

John Zaia, director of the Center for Gene Therapy at City of Hope, is working with TGen, and has other COVID-19-related projects happening as well.

Zaia is leading a research project at City of Hope, in collaboration with Altins lab, that could lead to development of a COVID-19 virus antibody neutralization test, which would quantify antibodies.

Zaia also has received a $750,000 grant from the California Institute for Regenerative Medicine for a clinical study on the use of blood plasma as a potential treatment for COVID-19.

Theyre doing what you could call qualitative and quantitative measurements of the nature of the antibody what does it actually bind to? Zaia said. The virus has this surface protein, the spike protein, but there are also other things the immune system might be seeing. It might be focused on one or more parts of the spike.

The CIRM project will focus on finding plasma donors to determine if theres any correlation between the outcome in the sick patient who received the plasma and the specific antibody that went in. It will focus on under-served areas.

Duarte-based City of Hope was founded in 1913 and is a founding member of the National Comprehensive Cancer Network. It has many sites throughout Southern California, and is investing $1 billion to establish clinics and a cancer center in Orange County. A clinic opened in Newport Beach in January, and a hospital dedicated to cancer treatment and research is slated for Irvine.

On the forefront of science, new discoveries are made every day and so much is still unknown.

I think the FDA said it best: Theres no way that one group could solve all the problems, do all the testing that needs to be done, Zaia said. The whole field is so new.

Theres a balance that must be struck between moving quickly and moving carefully, Altin said. We should know a lot in the next three months about how the antibody response looks, he said. Vaccine development will take much longer.

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Why does immune response to coronavirus save some, kill others? - East Bay Times

The Gene Therapies for Cancer Treatment market report provides a thorough analysis of this business landscape based on the consumption and production aspects. With respect to consumption, the report reviews the product consumption value as well as the product consumption volume alongside the individual sales trends of each product during the forecast period. In addition, details regarding the import and export graphs across the various geographies are also provided in the report.

According to Latest Research Report on Gene Therapies for Cancer Treatment Market size | Industry Segment by Applications (Cancer Research Centers,Diagnostic Laboratories,Cancer Hospitals andOthers), by Type (Somatic Cell Gene Therapy (SCGT) andGermline Gene Therapy (GGT), Regional Outlook, Market Demand, Latest Trends, Gene Therapies for Cancer Treatment Industry Share, Research Growth Forecast & Revenue by Manufacturers, The Leading Company Profiles, Growth Forecasts 2026.

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Based on the production aspect, the report covers the manufacturing of the product, its revenue, and gross margins garnered by the market majors. Variation in unit costs strategized by these manufacturers across various regional markets during the analysis period are also entailed in the report.

A brief of the regional outlook:

An overview of the product spectrum:

A gist of the application terrain:

Insights regarding the competitive terrain:

In summary, the Gene Therapies for Cancer Treatment market report is evaluated through several categorizations, including the basic industry definitions. Information pertaining the upstream raw materials, downstream buyers, and distribution channels of the competitors are discussed in the report. The study also examines the key drivers, restraints and opportunities that will impact the growth trends in the ensuing years.

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Key Questions Answered in the Report Include:

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Gene Therapies for Cancer Treatment Market Report, History and Forecast 2015-2026, Breakdown Data by Manufacturers, Key Regions, Types and Application...

People who are overweight and suffering from joint pain caused by osteoarthritis are often reluctant to exercise, even though physical activity can boost muscle strength and relieve pain. A new study suggests gene therapy may someday be a good option for those peopleand it may help them shed pounds, too.

Researchers at the Washington University School of Medicine gave young mice a single injection of the gene that makes follistatin, a protein that normally blocks another protein called myostatin, which modulates muscle growth. The therapy caused a significant buildup of muscle mass in the mice while also preventing obesity, the team reported in the journal Science Advances.

We've identified here a way to use gene therapy to build muscle quickly, said senior investigator Farshid Guilak, Ph.D., professor of orthopaedic surgery and director of research at Shriners Hospitals for Children St. Louis, in a statement. 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."

In fact, the mice didnt just build muscle, they also nearly doubled their strength without exercising any more than they usually did. Despite being fed a high-fat diet, they had fewer metabolic issues and stronger hearts than did animals that did not receive the follistatin gene. Their joints were healthier, with less cartilage damage and inflammatory markers than their untreated counterparts, the researchers reported.

Whats more, the Washington University team discovered that the gene therapy promoted the beiging of white fat, meaning it turned some unhealthy white adipose tissue into brown fat, which positively correlates with increased triglyceride clearance, normalized glucose level, and reduced inflammation, the researchers wrote in the study. Therefore, delivering the follistatin gene could serve as a very promising approach to induce beiging of [white adipose tissue] in obesity, they wrote.

RELATED: Could gene therapy be the solution to obesity and diabetes?

This is not the first time gene therapy has been proposed as a potential treatment for obesity and other metabolic diseases. Australian researchers demonstrated that removing the gene RCAN1 from mice, for example, helped turn white fat into brown fat. And a team in South Korea used the gene editing system CRISPR to remove the FABP4 gene from mice that had been fed a high-fat diet, resulting in a 20% loss of body weight and a reduction in insulin resistance.

The Washington University teams approach is distinctive in that it focuses on building muscle. But the researchers noted theyll have to do further studies to determine whether the gene therapy has any negative effect on heart muscle. Even though heart health improved in the mice, any thickening of the hearts walls could be dangerous over time.

Still, Guilak and his colleagues believe that follistatin gene therapy could be a promising approach to treating several conditions, including muscular dystrophy and other diseases that cause muscle wasting, they said in the study.

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Gene therapy cuts fat and builds muscle in sedentary mice on unhealthy diets - FierceBiotech

California-based Kriya Therapeutics announced on Tuesday that it concluded an $80.5 million Series A financing round, led by QVT, Dexcel Pharma, Foresite Capital, Bluebird Ventures, Narya Capital, Amplo, Paul Manning, and Asia Alpha. The company, which was founded in 2019, has a pipeline that includes multiple AAV-based gene therapies for the treatment of type 1 and type 2 diabetes, as well as obesity.

"There have been numerous successful gene therapies focused on rare monogenic diseases in recent years," said Shankar Ramaswamy, M.D., Co-Founder, Chairman, and CEO of Kriya Therapeutics. "We see tremendous potential to expand the field and apply gene therapy to highly prevalent serious diseases. We are focused on designing gene therapies using algorithmic tools, scalable infrastructure, and proprietary technology to optimize the efficacy and durability of our treatments. We look forward to accelerating the development of our pipeline, platform technologies, and internal GMP manufacturing capability with the funds raised in this Series A financing."

Kriya focuses on developing gene therapies for conditions that impact millions of patients. Its goal is to design one-time gene therapies to express therapeutic proteins within specific human tissues. Kriyas pipeline includes KT-A112, KT-A522, and KT-A832, all of which are investigational gene therapies.

Kriyas leadership team is composed of experts who have experience designing, developing and manufacturing successful gene therapies as well.

"Kriya is building a leading team and cutting-edge infrastructure to engineer best-in-class gene therapies for severe chronic conditions and accelerate their advancement into human clinical trials," said Roger Jeffs, Ph.D., Co-Founder and Vice Chairman of Kriya. "The company is committed to incorporating the latest advancements in the field into the design and development of its therapeutic constructs. Through its R&D laboratory capabilities in the Bay Area and in-house process development and manufacturing infrastructure in Research Triangle Park, I believe that Kriya will be uniquely positioned to become a leader in the gene therapy field."

Another company with a focus on gene therapy that recently came out of stealth mode is Dyno Therapeutics. On Monday, the Massachusetts-based organization announced that it is now eligible for more than $2 billion in upfront payments, research support and various milestones and options fees through its research-and-development and collaboration deals.

Dyno, which launched in 2018 with approximately $9 million in financing, has a technology platform built on the intellectual property that came from the laboratory of George Church. Church, who is the Robert Winthrop Professor of Genetics at Harvard Medical School, is a cofounder of Dyno.

At Dyno, we see a vast opportunity to expand the treatment landscape for gene therapies, said Eric D. Kelsic, co-founder and chief executive officer of Dyno. The success of gene therapy relies on the ability of vectors to safely and precisely deliver a gene to the intended target cells and tissues. Our approach addresses the major limitations of naturally occurring AAV vectors and creates optimized, disease-specific vectors for gene therapies with great curative potential. Our portfolio of R&D programs and newly-announced collaborations with leading gene therapy developers reflect the applicability of our AI-powered approach to improve treatments for patients and expand the number of treatable diseases with gene therapies.

Dyno has announced partnerships with Novartis and Sarepta Therapeutics thus far. With Sarepta, Dyno will design and discover novel AAV capsids to improve gene therapy for muscle diseases. Along with Novartis, Dyno will focus on developing improved AAV vectors for gene therapies for ocular diseases.

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Kriya Therapeutics to Focus on Gene Therapy with $80.5M in Funding - BioSpace

A gene therapy developer emerging from stealth mode said today it could generate more than $2 billion through collaborations launched with Novartis and Sarepta Therapeutics to develop treatments based on a delivery platform developed in the lab of George Church, PhD, of Harvard Medical School.

Dyno Therapeutics said it will partner with Novartis on research, development, and commercialization of new gene therapies for eye diseases incorporating improved adeno-associated virus (AAV) vectors. Separately, Dyno will collaborate with Sarepta on gene therapies for muscle diseases.

Both collaborations will apply Dynos CapsidMap platform, which uses artificial intelligence (AI) to design novel capsids that confer improved functional properties to AAV vectors. At the core of CapsidMap, according to Dyno, are advanced search algorithms applying machine learning and the companys large quantities of experimental data.

CapsidMap is designed to integrate DNA library synthesis and next generation DNA sequencing to measureinvivogene delivery properties in high throughput.The capsid platform is designed to expand the universe of diseases treatable via gene therapy by improving upon present-day AAV vectors, which are limited by delivery, immunity, packaging size, and manufacturing challenges.

Our portfolio of R&D programs and newly-announced collaborations with leading gene therapy developers reflect the applicability of our AI-powered approach to improve treatments for patients and expand the number of treatable diseases with gene therapies, Eric Kelsic, PhD, a former postdoc of Church who is Dynos CEO and Co-founder, said in a statement. We see a vast opportunity to expand the treatment landscape for gene therapies.

Dyno has an exclusive option to enter into a license agreement with Harvard University for the CapsidMap technology, which was developed in the lab of Church, a co-founder of Dyno and chairman of its scientific advisory board. Church is the Robert Winthrop Professor of Genetics at Harvard Medical School and a Core Faculty member at Harvards Wyss Institute for Biologically Inspired Engineering.

Church and other co-founders and members of his lab at HMS and the Wyss Institute carried out work that underpin Dynos approach to AAV capsid engineering, described in Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design, a paper published November 29, 2019, in the journal Science.

In that paper, Church, Kelsic, and two co-authors detailed how they mutated one-by-one each of the 735 amino acids within the AAV2 capsid, including all possible codon substitutions, insertions and deletions at each position. They generated a virus library containing about 200,000 variants and identified capsid changes that both maintained AAV2s viability and improved its homing potential (tropism) to specific organs in mice.

Unexpectedly, the team also discovered a new accessory protein hidden within the capsid-encoding DNA sequence that binds to the membrane of target cells, playing a significant role in viral production.

Our comprehensive, machine-guided design strategy generated viable mutants in a principled and high-throughput manner and is generalizable to other proteins and engineering challenges, the researchers reported. Applied to AAV, such methods now enable the systematic optimization of natural capsids into synthetic variants with enhanced properties for emerging gene therapies.

Under its partnership with Novartis, Dyno will be responsible for using AI technology and its suite of machine learning and experimental tools for the design and discovery of novel AAV capsids. Novartis agreed to conduct preclinical, clinical, and commercialization activities for the gene therapy product candidates created with the novel AAV capsids.

Dyno and Novartis did not disclose specific financial terms of their collaboration. They did say, however, that Novartis agreed to pay Dyno an upfront fee plus committed research funding and license fees. Dyno will be eligible to receive clinical, regulatory and sales milestone payments. Dyno will also receive royalties on worldwide net sales of any commercial products developed through the partnership.

Many eye diseases are ideally suited to being treated with gene therapies, and more opportunities can be opened with new and improved AAV vectors, Kelsic added. With their extensive ophthalmologic expertise, Novartis is an ideal partner to leverage Dynos platform to design AI-powered vectors to expand the impact of gene therapies for ocular diseases.

Under its collaboration with Sarepta, Dyno agreed to oversee the design and discovery of novel AAV capsids with improved functional properties for gene therapy, while Sarepta agreed to take responsibility for conducting preclinical, clinical and commercialization activities for gene therapy product candidates using the novel capsids.

Our agreement with Dyno provides us with another valuable tool to develop next-generation capsids for gene therapies to treat rare diseases, stated Doug Ingram, Sareptas president and CEO. By leveraging Dynos AI platform and Sareptas deep expertise in gene therapy development, our goal is to advance next-generation treatments with improved muscle-targeting capabilities.

Sarepta agreed to pay Dyno a total $40 million in in upfront, option, and license payments during the research phase of their collaboration. Should Sarepta develop and commercialize multiple candidates for multiple muscle diseases, Dyno said, it will be eligible for additional significant future milestone payments. Dyno will also receive royalties on worldwide net sales of any commercial products developed through the collaboration.

Dyno was launched in late 2018 with a $9 million financing co-led by Polaris Partners and CRV. Alan Crane, a co-founder of Dyno and entrepreneur partner at Polaris Partners, and Dylan Morris, general partner at CRV, have joined Dynos board, with Crane serving as Dynos executive chairman.

Dyno said it did not anticipate the need for additional fundraising, based on the significant financial resources made available through its collaborations.

Link:
Dyno Inks Up to $2B+ in Gene Therapy Partnerships with Novartis, Sarepta - Genetic Engineering & Biotechnology News

NEW YORK--(BUSINESS WIRE)--Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT) (Rocket), a clinical-stage company advancing an integrated and sustainable pipeline of genetic therapies for rare disorders, today presents new clinical data supporting longer-term efficacy and durability of gene therapy for Fanconi Anemia (FA) and Leukocyte Adhesion Deficiency-I (LAD-I) at the 23rd Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) being held virtually May 12-15, 2020. Two oral presentations highlight updates from the companys Phase 1/2 study of RP-L201 for the treatment of severe LAD-I and the Phase 1/2 study of RP-L102 Process A for the treatment of FA.

The latest additional data from both our LAD-I and FA programs demonstrate sustained engraftment and durable clinical impact, said Jonathan D. Schwartz, M.D., Chief Medical Officer and Senior Vice President of Rocket. These results further support the viability of gene therapy in LAD-I and FA, disorders in which bone marrow transplant is the primary curative option and is associated with high rates of toxicity.

Patients with severe LAD-I have neutrophil CD18 expression of less than 2% of normal, with extremely high mortality in early childhood, said Dr. Schwartz. In this first patient treated with RP-L201 using Process B, an increase from less than 1% to 47% CD18 expression sustained over six months demonstrates that RP-L201 has the potential to correct the neutrophil deficiency that is the hallmark of LAD-I. We are also pleased with the continued visible improvement of multiple disease-related skin lesions. These results lend further support to the applicability of Process B across the lentiviral portfolio. The second patient has also recently been treated, and we look forward to completing the Phase 1 portion of the registrational trial for this program.

Dr. Schwartz continued, In our FA program, patients followed for a year or more after treatment with RP-L102 Process A continue to demonstrate durable engraftment and hematologic correction, without the use of pre-treatment conditioning regimens. All six patients who received minimally adequate drug product and were followed for more than one year display sustained and progressive engraftment. Notably, hemoglobin levels have normalized to baseline in two patients treated. Todays update not only gives us confidence as we transition to our improved Process B drug product, but also supports the potential of gene therapy in the absence of any conditioning regimen as a definitive hematologic treatment for FA. The ability to treat patients without the side effects associated with allogeneic transplant or the use of genotoxic conditioning, and to restore blood cell counts is a major milestone for the FA scientific community.

Details on Rockets oral presentations at ASGCT:

Title: A Phase 1/2 Study of Lentiviral-mediated Ex-vivo Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I (LAD-I): Initial Results from the First Treated Patient Session: HSPC Gene Therapies for Blood and Immune DisordersPresenter: Donald B. Kohn, M.D., Professor of Microbiology, Immunology and Molecular Genetics, Pediatrics (Hematology/Oncology), Molecular and Medical Pharmacology, member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and principal investigator of the Phase 1 trialDate: Tuesday May 12, 2020Time: 4:30 p.m. - 4:45 p.m. EDT

Additional results from the first patient treated with RP-L201 for LAD-I continue to demonstrate evidence of safety and potential efficacy. Analyses of peripheral vector copy number (VCN) and CD18-expressing neutrophils were performed six months post treatment with RP-L201 to evaluate engraftment and phenotypic correction. The patient demonstrated peripheral blood VCN levels of 1.3 and CD18-expression of 47%, which is sustained from the 45% expression observed three months post treatment; pretreatment CD18 expression was <1%. The drug product VCN was 3.8. Additionally, the patient continues to display visible improvement of skin lesions. No safety or tolerability issues related to RP-L201 administration have been identified to date.

RP-L201 was in-licensed from the Centro de Investigaciones Energticas, Medioambientales y Tecnolgicas (CIEMAT), Centro de Investigacin Biomdica en Red de Enfermedades Raras (CIBERER) and Instituto de Investigacin Sanitaria Fundacin Jimnez Daz (IIS-FJD). The lentiviral vector was developed in a collaboration between The University College of London (UCL) and CIEMAT.

Title: Updated Results of a European Gene Therapy Trial in Fanconi Anemia Patients, Subtype ASession: HSPC Gene Therapies for Blood and Immune DisordersPresenter: Juan A. Bueren, Ph.D., Scientific Director of the FA gene therapy program and Head of the Hematopoietic Innovative Therapies Division at CIEMAT in Spain / CIBERER / IIS-FJD Date: Tuesday May 12, 2020Time: 4:45 p.m. - 5:00 p.m. EDT

Nine pediatric patients have been enrolled and treated in the Phase 1/2 clinical trial of RP-L102 Process A for the treatment of Fanconi Anemia, seven of whom are evaluable at or beyond the one year mark following treatment. The first four patients (02002, 02004, 02005 and 02006) exhibit robust and durable engraftment, continued hematologic correction and blood count stabilization. Importantly, hemoglobin levels for patients 02002 and 02006 have increased to a healthy, normal range; these patients received more optimal product consistent with the minimal dose criteria established for the Process B registrational program. Two additional patients (02008 and 02013) who have been followed for a year or more after treatment display early evidence of engraftment, as measured by increases in peripheral blood VCNs. Patient 02007 received a lower than optimal dose and is beginning to demonstrate preliminary signs of engraftment. Blood counts are not yet available in these patients. Two patients, patients 01003 and 02009, have not been included in this analysis. Patient 02009 is only six months post treatment and will continue to be followed. Patient 01003 received a drug product that did not meet full release criteria due to a technical issue this was a one-time lab-specific issue that was addressed. To date, no patients in this trial have undergone allogeneic bone marrow transplant.

RP-L102 is being developed in conjunction with CIEMAT, CIBERER and IIS-FJD.

The presentations will be made available on Rockets website at http://www.rocketpharma.com/asgct-presentations/ following presentation at the conference.

About Leukocyte Adhesion Deficiency-ISevere Leukocyte Adhesion Deficiency-I (LAD-I) is a rare, autosomal recessive pediatric disease caused by mutations in the ITGB2 gene encoding for the beta-2 integrin component CD18. CD18 is a key protein that facilitates leukocyte adhesion and extravasation from blood vessels to combat infections. As a result, children with severe LAD-I are often affected immediately after birth. During infancy, they suffer from recurrent life-threatening bacterial and fungal infections that respond poorly to antibiotics and require frequent hospitalizations. Children who survive infancy experience recurrent severe infections including pneumonia, gingival ulcers, necrotic skin ulcers, and septicemia. Without a successful bone marrow transplant, mortality in patients with severe LAD-I is 60-75% prior to the age of 2 and survival beyond the age of 5 is uncommon. There is a high unmet medical need for patients with severe LAD-I.

Rockets LAD-I research is made possible by a grant from the California Institute for Regenerative Medicine (Grant Number CLIN2-11480). The contents of this press release are solely the responsibility of Rocket and do not necessarily represent the official views of CIRM or any other agency of the State of California.

About Fanconi AnemiaFanconi Anemia (FA) is a rare pediatric disease characterized by bone marrow failure, malformations and cancer predisposition. The primary cause of death among patients with FA is bone marrow failure, which typically occurs during the first decade of life. Allogeneic hematopoietic stem cell transplantation (HSCT), when available, corrects the hematologic component of FA, but requires myeloablative conditioning. Graft-versus-host disease, a known complication of allogeneic HSCT, is associated with an increased risk of solid tumors, mainly squamous cell carcinomas of the head and neck region. Approximately 60-70% of patients with FA have a Fanconi Anemia complementation group A (FANCA) gene mutation, which encodes for a protein essential for DNA repair. Mutation in the FANCA gene leads to chromosomal breakage and increased sensitivity to oxidative and environmental stress. Increased sensitivity to DNA-alkylating agents such as mitomycin-C (MMC) or diepoxybutane (DEB) is a gold standard test for FA diagnosis. Somatic mosaicism occurs when there is a spontaneous correction of the mutated gene that can lead to stabilization or correction of a FA patients blood counts in the absence of any administered therapy. Somatic mosaicism, often referred to as natural gene therapy provides a strong rationale for the development of FA gene therapy because of the selective growth advantage of gene-corrected hematopoietic stem cells over FA cells1.

1Soulier, J.,et al. (2005) Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway. Blood 105: 1329-1336

About Rocket Pharmaceuticals, Inc.Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT) (Rocket) is advancing an integrated and sustainable pipeline of genetic therapies that correct the root cause of complex and rare disorders. The companys platform-agnostic approach enables it to design the best therapy for each indication, creating potentially transformative options for patients afflicted with rare genetic diseases. Rocket's clinical programs using lentiviral vector (LVV)-based gene therapy are for the treatment of Fanconi Anemia (FA), a difficult to treat genetic disease that leads to bone marrow failure and potentially cancer, Leukocyte Adhesion Deficiency-I (LAD-I), a severe pediatric genetic disorder that causes recurrent and life-threatening infections which are frequently fatal, and Pyruvate Kinase Deficiency (PKD) a rare, monogenic red blood cell disorder resulting in increased red cell destruction and mild to life-threatening anemia. Rockets first clinical program using adeno-associated virus (AAV)-based gene therapy is for Danon disease, a devastating, pediatric heart failure condition. Rockets pre-clinical pipeline program is for Infantile Malignant Osteopetrosis (IMO), a bone marrow-derived disorder. For more information about Rocket, please visit http://www.rocketpharma.com.

Rocket Cautionary Statement Regarding Forward-Looking StatementsVarious statements in this release concerning Rocket's future expectations, plans and prospects, including without limitation, Rocket's expectations regarding its guidance for 2020 in light of COVID-19, the safety, effectiveness and timing of product candidates that Rocket may develop, to treat Fanconi Anemia (FA), Leukocyte Adhesion Deficiency-I (LAD-I), Pyruvate Kinase Deficiency (PKD), Infantile Malignant Osteopetrosis (IMO) and Danon Disease, and the safety, effectiveness and timing of related pre-clinical studies and clinical trials, may constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995 and other federal securities laws and are subject to substantial risks, uncertainties and assumptions. You should not place reliance on these forward-looking statements, which often include words such as "believe," "expect," "anticipate," "intend," "plan," "will give," "estimate," "seek," "will," "may," "suggest" or similar terms, variations of such terms or the negative of those terms. Although Rocket believes that the expectations reflected in the forward-looking statements are reasonable, Rocket cannot guarantee such outcomes. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Rocket's ability to monitor the impact of COVID-19 on its business operations and take steps to ensure the safety of patients, families and employees, the interest from patients and families for participation in each of Rockets ongoing trials, our expectations regarding when clinical trial sites will resume normal business operations, our expectations regarding the delays and impact of COVID-19 on clinical sites, patient enrollment, trial timelines and data readouts, our expectations regarding our drug supply for our ongoing and anticipated trials, actions of regulatory agencies, which may affect the initiation, timing and progress of pre-clinical studies and clinical trials of its product candidates, Rocket's dependence on third parties for development, manufacture, marketing, sales and distribution of product candidates, the outcome of litigation, and unexpected expenditures, as well as those risks more fully discussed in the section entitled "Risk Factors" in Rocket's Quarterly Report on Form 10-Q for the quarter ended March 31, 2020, filed May 8, 2020 with the SEC. Accordingly, you should not place undue reliance on these forward-looking statements. All such statements speak only as of the date made, and Rocket undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise.

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Rocket Pharmaceuticals Presents Positive Updates on FA and LAD-I Gene Therapy Programs at the 23rd Annual Meeting of the American Society of Gene and...

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a pioneer in T-cell immunotherapy leveraging its novel allogeneic EBV T-cell platform to develop transformative therapies for patients with severe diseases including solid tumors, hematologic cancers and autoimmune diseases, today announced the appointment of immunology and cell & gene therapy expert Maria Grazia Roncarolo, MD, to the Board of Directors.

Dr. Roncarolo is the George D. Smith Professor in Stem Cell and Regenerative Medicine, Professor of Pediatrics and Medicine, Director of the Center for Definitive and Curative Medicine, and Co-Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University.

In 2014, Dr. Roncarolo established the Stanford Center for Definitive and Curative Medicine. The center, which is dedicated to the development of innovative stem cell and gene therapies for patients with currently incurable diseases, spans a wide range of bench and clinical research activities from basic biology through translational research and features its own GMP cell processing and Phase 1 study units.

I am thrilled to have one of the worlds leading experts in immunology and T cells, Dr. Roncarolo, bringing to our Board her experience and strategic vision in cell therapy and gene editing as well as her passion for transformative immunotherapies, said Pascal Touchon, President and Chief Executive Officer of Atara. She has dedicated her life to caring for patients with severe immunological and hematological diseases and has an impressive record in translating scientific discoveries in cell and gene therapy into novel treatments which aligns very well with Ataras mission.

Dr. Roncarolo has served as the primary investigator in several landmark trials involving the development of innovative stem cell- and gene-based therapies. She worked at DNAX Research Institute for Molecular and Cellular Biology in Palo Alto for several years, where she contributed to the discovery of novel cytokines, cell-signaling molecules that are part of the immune response. She studied the role of these cytokines in inducing immunological tolerance and in promoting stem cell growth and differentiation. As Director of the Telethon Institute for Cell and Gene Therapy and the San Raffaele Scientific Institute in Milan, Dr. Roncarolo was the principal investigator leading the successful gene therapy trial in SCID, a severe life threatening disorder in which patients lack an enzyme critical to DNA synthesis.

Beyond studying new therapies, Dr. Roncarolo has also helped elucidate drivers of disease at the molecular and cellular level, as she has investigated the mechanisms of immune-mediated diseases throughout her career and helped advance the understanding of immunological tolerance. Dr. Roncarolo was the recipient of the outstanding achievement award from the European Society of Gene and Cell Therapy (ESGCT) in 2010 and from the American Society of Gene and Cell Therapy (ASGCT) in 2017. She is currently the president of the Federation of Clinical Immunology Societies.

About Atara Biotherapeutics

Atara Biotherapeutics, Inc. (@Atarabio) is a pioneer in T-cell immunotherapy leveraging its novel allogeneic EBV T-cell platform to develop transformative therapies for patients with severe diseases including solid tumors, hematologic cancers and autoimmune disease. With our lead program in Phase 3 clinical development, Atara is the most advanced allogeneic T-cell immunotherapy company and intends to rapidly deliver off-the-shelf treatments to patients with high unmet medical need. Our platform leverages the unique biology of EBV T cells and has the capability to treat a wide range of EBV-associated diseases, or other severe diseases through incorporation of engineered CARs (chimeric antigen receptors) or TCRs (T-cell receptors). Atara is applying this one platform to create a robust pipeline including: tab-cel (tabelecleucel) in Phase 3 development for Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV+ PTLD); ATA188, a T-cell immunotherapy targeting EBV antigens as a potential treatment for multiple sclerosis; and multiple next-generation chimeric antigen receptor T-cell (CAR T) immunotherapies for both solid tumors and hematologic malignancies. Improving patients lives is our mission and we will never stop working to bring transformative therapies to those in need. Atara is headquartered in South San Francisco and our leading-edge research, development and manufacturing facility is based in Thousand Oaks, California. For additional information about the company, please visit atarabio.com and follow us on Twitter and LinkedIn.

Forward-Looking Statements

This press release contains or may imply "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. Because such statements deal with future events and are based on Atara Biotherapeutics' current expectations, they are subject to various risks and uncertainties and actual results, performance or achievements of Atara Biotherapeutics could differ materially from those described in or implied by the statements in this press release. These forward-looking statements are subject to risks and uncertainties, including those discussed in Atara Biotherapeutics' filings with the Securities and Exchange Commission (SEC), including in the Risk Factors and Managements Discussion and Analysis of Financial Condition and Results of Operations sections of the Companys most recently filed periodic reports on Form 10-K and Form 10-Q and subsequent filings and in the documents incorporated by reference therein. Except as otherwise required by law, Atara Biotherapeutics disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date hereof, whether as a result of new information, future events or circumstances or otherwise.

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Atara Biotherapeutics Announces Appointment of Cell & Gene Therapy Expert Maria Grazia Roncarolo, MD to Board of Directors - Business Wire

DUBLIN Dyno Therapeutics Inc., an early stage gene therapy firm applying artificial intelligence to advanced capsid engineering, has entered partnerships with Novartis AG and Sarepta Therapeutics Inc., in ophthalmic indications and muscle diseases, respectively, which have more than $2 billion in biobucks attached. Further financial details are scant, although it could receive more than $40 million in up-front, option and license payments during the research phase of the Sarepta alliance. The two deals are evidence of the market appetite for improved adeno-associated viral vectors. We had a significant amount of interest even before the company was formed, Dyno CEO and co-founder Eric Kelsic told BioWorld.

The phase III pivotal trial of mavacamten, an oral, allosteric cardiac myosin modulator for treating symptomatic, obstructive hypertrophic cardiomyopathy, from Myokardia Inc., of Brisbane, Calif., hit its primary and all secondary endpoints. The data show mavacamten was well-tolerated and demonstrated safety results comparable to placebo. Ninety-eight percent of patients enrolled completed the study. The company stock (NASDAQ:MYOK) was met by enthusiasm midday Monday, as shares swelled by 62%. Myokardia said it plans to submit an NDA in the first quarter of 2021. Myokardia is developing mavacamten to treat conditions in which excessive cardiac contractility and impaired diastolic filling of the heart are the underlying cause.

After being hit with the major market meltdown during March, public biopharmaceutical companies developing new medicines put that behind them with a dramatic surge in valuations in April. As a result, the BioWorld Drug Developers index recorded an almost 20% increase during the period, with that momentum continuing into early May.

By delivering the protein follistatin via gene therapy, researchers at Washington University in St. Louis were able to increase skeletal muscle mass, decrease inflammation and reverse obesity-related arthritis in mice who developed osteoarthritis as a result of a high-fat diet. They reported their results in the May 8, 2020, online issue of Science Advances.

HONG KONG The Japanese government is tightening its grip on its listed companies, including those working on promising COVID-19 treatments. On May 8, the Japanese Ministry of Finance releaseda list of 518 companies that would be subject to stricter restrictions on receiving foreign investments. Starting on June 7, foreign investors buying a stake of 1% or more in Japanese firms will be pre-screened, compared with the previous limit of 10%. In a statement, the ministry said the move was related to the degree of impact of the investment on maintaining the basis of production and technologies in the business sectors that relate to protection of national security, maintenance of public order, or safeguard of public safety.

DUBLIN Tolerogenixx GmbH is on track to move its cell-based immune tolerance induction therapy for kidney transplant recipients into a 200-patient phase IIb trial, following the publication of promising data from a phase Ib trial in 10 patients, in which all participants had a successful transplant at one-year follow-up, including those in a high-dose group on a reduced immunosuppression regimen.

Having a COVID-19 therapy approved through an emergency use authorization (EUA) is not the same as having access to it, even if its free. With one-third of the COVID-19 cases confirmed globally as of today and 28.5% of the deaths, the U.S. is getting 40% of the 1.5 million doses of remdesivir Gilead Sciences Inc. is donating worldwide. The federal government last week began doling out the 607,000 doses to the states, which are then charged with distributing them to the hospitals with the greatest need. But given the supply and manufacturing timeline for the first drug granted an EUA to treat severe COVID-19 cases, more than 300,000 eligible U.S. patients likely will not have access to the drug through the end of July, said Brian Abrahams, a senior analyst with RBC Capital Markets LLC.

HONG KONG South Koreas Hanmi Pharmaceutical Co. Ltd. has filed a new drug approval application for Rolontis (eflapegrastim) with the countrys Ministry of Food and Drug Safety. Rolontis, a biologic to treat neutropenia, is the first of its kind in South Korea and, according to Hanmi, the first to be developed using the companys Lapscovery platform.

About 15 months after closing its multibillion-dollar acquisition of Loxo Oncology Inc., Eli Lilly and Co. has secured an accelerated FDA approval for the first of the deal's headline assets, the RET kinase inhibitor selpercatinib, now branded as Retevmo. The green light, following a priority review, allows for marketing of the drug as a treatment for three types of tumors non-small-cell lung cancer, medullary thyroid cancer and other types of thyroid cancers in patients whose tumors have a rearranged during transfection alteration. The decision arrived well ahead of an earlier-projected third-quarter decision by the agency.

Three biopharma drugs are up for FDA approval this week, including one new chemical entity, dasotraline, from Sunovion Pharmaceuticals Inc. to treat binge eating disorder, and two other candidates that are part of supplemental filings for expanded oncology indications. Sunovions drug and Blueprint Medicines Corp.s Ayvakit (avapritinib) to treat fourth-line gastrointestinal stromal tumors (GIST), have PDUFA dates set for May 14, while Clovis Oncology Inc.s Rubraca (rucaparib) for prostate cancer is scheduled for May 15.

The articles from BioWorlds ongoing coverage of the COVID-19 coronavirus outbreak are available at http://www.bioworld.com/coronavirus. Note that we have added three critical tables which are constantly updated:

4D Pharma, 9 Meters, Abbvie, ADC, Amag, Appili, Artara, Astrazeneca, Bellerophon, Biomarin, Bluebird, Bridgebio, Burning Rock, Cellect, Cocrystal, Crispr, Daicchi, Dar, Faron, Histogen, Hummingbird, Infinity, Inmune, Intercept, Jazz, Kiniksa, Kura, Lilly, Merck, Mimedx, Myokardia, Navidea, Noxxon, Orexo, Oyster Point, Pliant, Plus, Portage, Protagonist, Protalix, Regeneron, Relief, Ritter, Strongbridge, Themis, Tiburio, Tolerogenixx, Tracon, Vertex

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Novartis, Sarepta join Dyno's enterprise to boldly go to new gene therapy frontier - BioWorld Online

The Cell and Gene Therapy Catapult (CGT Catapult) and Kyoto, Japan-based CiRA Foundation are launching a new collaborative research project focused on induced pluripotent stem (iPS) cell characterisation.

With the move, the groups are hoping to further the application of iPS cell technologies for the manufacture of regenerative medicine products.

The potential of distinct iPS cell lines for differentiation into specific cell types is usually biased towards some cell line-specificity which, the parties note, is very difficult to predict. As such, in order to select an appropriate iPS cell line for clinical trials it is necessary to differentiate several candidate cell lines, which is time-consuming.

CGT Catapult and CiRA plan to explore novel methods of evaluating cell differentiation and aim to establish reliable tests to predict the potential of iPS cell to differentiation bias, a capability that would help to advance the use of iPS cells for regenerative medicine products.

We are honoured to collaborate with CiRA Foundation, an organisation with world-leading capabilities in iPS cell technology, and to be the first group to utilise CiRAs innovative iPS cell lines outside of Japan, said CGT's chief executive Matthew Durdy

This is a truly exciting project to help further the application and manufacture of iPS cells into cell therapies. We look forward to progressing this promising research together, which has potential benefits for the global advanced therapies industry.

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Cell and Gene Therapy Catapult links with Japan's CiRA Foundation - PharmaTimes

For its first quarter ended March 31, 2020, the Maryland-based company, reported revenue of $1.9 million, compared to $0.4 million a year earlier

Inc (), a global biotech company focused on accelerating and transforming the delivery of cell and gene therapies, posted first-quarter results on Monday that saw its revenue soar 348% year-over-year driven by its Cell and Gene Therapy (CGT) Biotech platform.

For its first quarter ended March 31, 2020, the Germantown, Maryland-based company, reported revenue of $1.9 million, compared to $0.4 million in the first quarter of 2019.

Orgenesis achieved net income of $75.6 million, or $4.23 per share, reflecting the sale of subsidiary Masthercell Global Inc, a contract development manufacturing organization (CDMO).

READ:Orgenesis boss Vered Caplan makes top 20 list of inspirational leaders in advanced medicine

On February 11, Orgenesis completed the successful sale of its CDMO business to Somerset, New Jersey-based Catalent Pharma Solutions, for around $127 million.

As a result, Orgenesis reported cash and equivalents of $107.1 million as of March 31, 2020.

In a statement accompanying the numbers, Orgenesis CEO Vered Caplan said: 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, she added.

The companys CGT Biotech platform consists of three core elements:point-of care Therapeutics, point-of care Technologies, and point-of care Network.

Caplan also noted that earlier this year, the company struck collaboration agreements with two leading healthcare research institutes in the US.

We plan to utilize our point-of-care Network to support their growing development and processing needs in order to advance and accelerate cell and gene-based clinical therapeutic research, said Caplan.

Orgenesis is using the Masthercell sale proceeds to expand the companys point-of-care cell therapy business. The biotech is currently focused on therapies which span a wide range of treatments.

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, said Caplan.

Specifically, we are focusing on immune-oncology, metabolic and autoimmune diseases, as well as anti-viral therapies.

Orgenesis also recently completed the acquisition of Tamir Biotechnology and its broad-spectrum antiviral platform, ranpirnase in a cash and stock deal for roughly $21 million. The company will use ranpirnase to target human papillomavirus (HPV), which causes genital warts.

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, said Caplan.

Going forward, Orgenesis plans to move the program through a Phase 2b trial in the US.

Meanwhile, the Orgenesis boss said the company has received a nod from regulators to keep research alive at its labs during the coronavirus (COVID-19) pandemic.

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, said Caplan.

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.

At the start of April, Orgenesis teamed up with regenerative medicine and cell therapy firm RevaTis on a new joint venture to produce certain stem cells. The two firms plan to leverage Orgenesiss autologous CGT Biotech platform to advance clinical trials.

Under the deal, RevaTis and Orgenesis will use the formers patented technique to obtain muscle-derived mesenchymal stem cells (mdMSC) as a source of exosomes and various 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, said Caplan.

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.

Contact the author Uttara Choudhury at [emailprotected]

Follow her on Twitter: @UttaraProactive

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Orgenesis sees 1Q revenue rocket driven by its Cell and Gene Therapy Biotech platform - Proactive Investors USA & Canada

Amber Freeds singular mission is to help scientists develop a treatment for her son. But the pandemic has put the success of that mission into question.

Freed is a mother to twins Riley and Maxwell, who just turned 3 this year. Riley is a healthy toddler. But Maxwell has a rare genetic disease that has led to delays in his development. Hes nonverbal, and he has a movement disorder. The condition responsible for these symptoms is called SLC6A1, after the gene thats affected, and Maxwell was only the 34th person in the world to get this diagnosis. if left untreated, the disease could soon cause debilitating epilepsy.

When doctors broke the news of the diagnosis to Freed, they told her there was no treatment or cure for her son, and that her family would have to prepare to live with Maxwells condition. But Amber didnt accept that.

Every instinct in my body said, Youll have your whole lifetime to cry for yourself, Freed said. At this exact moment, you put your feelings and sadness aside. This isnt about you. This is about Maxwell. And you fight like the third monkey on the loading deck to Noahs Ark, and its starting to rain.

This is how Freeds quest began. She taught herself microbiology, so she could understand her sons condition. She lobbied scientists to take up the research, which wasnt on their radar given how rare the disease is. She convinced scientists in China to make genetically engineered mice that could be sent to the US and act as a model of Maxwells disease. And she fundraised a necessary step given the high cost of the gene therapy research.

All told, shes raised more than $1 million. What were doing will be the building blocks of all gene therapies to come after us, Freed told Arielle Duhaime-Ross on an episode of Reset in January.

Even though she was racing against time, she was optimistic that Maxwell would be treated this year, as experiments on the genetically modified mice were about to begin.

Then the pandemic hit.

Covid-19 has brought most non-coronavirus medical research to a halt, and closed labs.

I never anticipated or thought something like this could happen, Freed said, but also it was a state of devastation like I felt when Maxwell was originally diagnosed that lightning hit us. The unthinkable happened. And here, lightning has hit again. A black swan event for the world that no one could have anticipated.

Freed came back to Reset to talk about the impact of the pandemic on Maxwell and her family as well as rare disease research as a whole. Listen to the full episode below.

The episode also features a conversation with BuzzFeed science reporter Dan Vergano, who first wrote about Ambers story and who talks about how the closure has impacted thousands of other kids with rare diseases, as well as clinical trials for other types of medical research.

Listen and read more:

Listen to the original Reset story from January

Dan Verganos reporting on this story for BuzzFeed

Back in January, Dans piece on how the mice were being used to develop a treatment

Milestones for Maxwell, Amber Freeds website

Original post:
A treatment for this toddlers rare genetic condition was in sight. Then the pandemic hit. - Vox.com

DetailsCategory: More NewsPublished on Wednesday, 06 May 2020 09:49Hits: 453

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.

Request a sample Report of The Future of Gene Therapy Market at: https://www.marketstudyreport.com/request-a-sample/1695032?utm_source=jewishlifenews&utm_medium=RV

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.

Purchase full report of The Future of Gene Therapy market at: https://www.marketstudyreport.com/securecheckout/paymenta/1695032?utm_source=jewishlifenews&utm_medium=RV?msfpaycode=sumsf

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.

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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

Facts & Factors Market Researchadded a recent report onCell and Gene Therapy Consumables Market By Product Type (Kits & Buffers, Diagnostic Assay, Culture Medium, and Cryopreservation Media) and By Application/ Therapeutics (Cardiovascular, Urology, Dermatology, Critical Care, Respiratory, Endocrine & Metabolic, Neuroscience, Hematology & Oncology, Obstetrics, Immunology, and Gastroenterology): Global Industry Perspective, Comprehensive Analysis, and Forecast, 2018 2027to its research database. The Cell and Gene Therapy Consumables Market research report is an output of a brief assessment and an extensive analysis of practical data collected from the global industry.

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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.

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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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