Category Archives: Genetic Therapy

EVRY, France--(BUSINESS WIRE)--Atamyo Therapeutics, a biotechnology company focused on the development of new-generation gene therapies targeting neuromuscular diseases, today announced the dosing with ATA-100 of a first patient in a phase 1/2 clinical study in FRKP-related limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9).

This is an exciting milestone for our company but most importantly, if this clinical trial is successful, it could have a life-changing impact for patients affected by LGMD-R9, said Stephane Degove, Chief Executive Officer and Co-Founder of Atamyo Therapeutics.

This clinical trial (EudraCT 2021-004276-33, NCT05224505) is a multicenter, Phase 1/2 study evaluating safety, pharmacodynamic, efficacy, and immunogenicity of intravenous ATA-100, a single-dose Adeno-Associated Virus (AAV) vector carrying the human FKRP transgene.

This study will consist of 2 phases: an open-label dose escalation phase (Stage 1) and a double-blind placebo controlled, randomized phase (Stage 2).

LGMD-R9 is a severe progressive and debilitating disease with no approved treatment, said Pr. John Vissing, Director of the Copenhagen Neuromuscular Center at the National Hospital, Rigshospitalet, in Copenhagen, where the first patient was dosed, and principal investigator of this trial. This experimental treatment represents a new hope for the patients. It is a great motivation to know that the work we are doing here has the potential to make a life-changing difference.

After the first patient dosed in Copenhagen, we are now expecting recruitments at the two other approved clinical sites (Paris, FR, and Newcastle, UK) to complete enrollment of the dose escalation phase (Stage 1) of the study. For Stage 2 (after dose selection), we plan to open additional clinical sites in Europe and in the United States, said Dr. Sophie Olivier, Chief Medical Officer of Atamyo.

About the LGMD-R9 program ATA-100

ATA-100 is a one-time gene replacement therapy for LGMD-R9/2I based on the research of Dr. Isabelle Richard, who heads the Progressive Muscular Dystrophies Laboratory at Genethon (UMR 951 INSERM/Genethon/UEVE). ATA-100 has been awarded Orphan Drug Designation status by the U.S. Food and Drug Administration and the European Medicines Agency.

LGMD2I/R9 is a rare genetic disease caused by mutations in the gene that produces fukutin-related protein (FKRP). It affects an estimated 5,000 people in the US and Europe. Symptoms appear around late childhood or early adulthood. Patients suffer from progressive muscular weakness leading to loss of ambulation. They also are prone to respiratory impairment and myocardial dysfunction. There are currently no curative treatments for LGMDR9.

About Atamyo Therapeutics

Atamyo Therapeutics is a clinical-stage biopharma focused on the development of a new generation of effective and safe gene therapies for neuromuscular diseases. A spin-off of gene therapy pioneer Genethon, Atamyo leverages unique expertise in AAV-based gene therapy and muscular dystrophies from the Progressive Muscular Dystrophies Laboratory at Genethon. Atamyos most advanced programs address different forms of limb-girdle muscular dystrophies (LGMD). The name of the company is derived from two words: Celtic Atao which means Always or Forever and Myo which is the Greek root for muscle. Atamyo conveys the spirit of its commitment to improve the life of patients affected by neuromuscular diseases with life-long efficient treatments. For more information visit http://www.atamyo.com

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Atamyo Therapeutics Announces First Patient Dosed with ATA-100 Gene Therapy in LGMD-R9 Clinical Trial - Business Wire

New York, Sept. 29, 2022 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Viral Vector Manufacturing, Non-Viral Vector Manufacturing and Gene Therapy Manufacturing Market by Scale of Operation, Type of Vector, Application Area, Therapeutic Area, and Geographical Regions : Industry Trends and Global Forecasts, 2022-2035" - https://www.reportlinker.com/p06323417/?utm_source=GNW In fact, in 2021, cell and gene therapy developers raised capital worth more than USD 20 billion, registering an increase of 19% from the amount raised in 2020 (~USD 17 billion). It is worth highlighting that, in February 2022, the USFDA approved second CAR-T therapy, CARVYKTI, developed by Johnson and Johnson, which can be used for the treatment of relapsed or refractory multiple myeloma. Additionally, close to 1,500 clinical trials are being conducted, globally, for the evaluation of cell and gene therapies. Over time, it has been observed that the clinical success of these therapies relies on the design and type of gene delivery vector used (in therapy development and / or administration). At present, several innovator companies are actively engaged in the development / production of viral vectors and / or non-viral vectors for cell and gene therapies. In this context, it is worth mentioning that, over the past few years, multiple viral vector and non-viral vector based vaccine candidates have been developed against COVID-19 (caused by novel coronavirus, SARS-CoV-2) and oncological disorders; this is indicative of lucrative opportunities for companies that have the required capabilities to manufacture vectors and gene therapies.

The viral and non-viral vector manufacturing landscape features a mix of industry players (well-established companies, mid-sized firms and start-ups / small companies), as well as several academic institutes. It is worth highlighting that several companies that have the required capabilities and facilities to manufacturing vectors for both in-house requirements and offer contract services (primarily to ensure the optimum use of their resources and open up additional revenue generation opportunities) have emerged in this domain. Further, in order to produce more effective and affordable vectors, several stakeholders are integrating various novel technologies; these technologies are likely to improve the scalability and quality of the resultant therapy. In addition, this industry has also witnessed a significant increase in the partnership and expansion activities over the past few years, with several companies having been acquired by the larger firms. Given the growing demand for interventions that require genetic modification, the vector and gene therapy manufacturing market is poised to witness substantial growth in the foreseen future.

SCOPE OF THE REPORTThe Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market (5th Edition) by Scale of Operation (Preclinical, Clinical and Commercial), Type of Vector (AAV Vector, Adenoviral Vector, Lentiviral Vector, Retroviral Vector, Plasmid DNA and Others), Application Area (Gene Therapy, Cell Therapy and Vaccine), Therapeutic Area (Oncological Disorders, Rare Disorders, Neurological Disorders, Sensory Disorders, Metabolic Disorders, Musco-skeletal Disorders, Blood Disorders, Immunological Diseases, and Others), and Geographical Regions (North America, Europe, Asia Pacific, MENA, Latin America and Rest of the World): Industry Trends and Global Forecasts, 2022-2035 report features an extensive study of the rapidly growing market of vector and gene therapy manufacturing, focusing on contract manufacturers, as well as companies having in-house manufacturing facilities. The study presents an in-depth analysis of the various firms / organizations that are engaged in this domain, across different regions of the globe. Amongst other elements, the report includes:An overview of the current status of the market with respect to the players engaged (both industry and non-industry) in the manufacturing of viral, non-viral and other novel types of vectors and gene therapies. It features information on the year of establishment, company size, location of headquarters, type of product manufactured (vector and gene therapy / cell therapy / vaccine), location of manufacturing facilities, type of manufacturers (in-house and contract services), scale of operation (preclinical, clinical and commercial), type of vector manufactured (AAV, adenoviral, lentiviral, retroviral, plasmid DNA and others) and application area (gene therapy, cell therapy, vaccine and others).An analysis of the technologies offered / developed by the companies enagaged in this domain, based on the type of technology (viral vector related platform, non-viral vector related platform and others), type of manufacturer (vector manufacturing, gene delivery, product manufacturing, transduction / transfection, vector packaging and other), scale of operation (preclinical, clinical and commercial), type of vector involved (AAV, adenoviral, lentiviral, retroviral, non-viral and other viral vectors), application area (gene therapy, cell therapy, vcaccine and others). It also highlights the most prominent players within this domain, in terms of number of technologies.A region-wise, company competitiveness analysis, highlighting key players engaged in the manufacturing of vectors and gene therapies, across key geographical areas, featuring a four-dimensional bubble representation, taking into consideration supplier strength (based on experience in this field), manufacturing strength (type of product manufactured, number of manufacturing facilites and number of application areas), service strength (scale of operation, number of vectors manufactured and geographical reach) and company size (small, mid-sized and large).Elaborate profiles of key players based in North America, Europe and Asia-Pacific (shortlisted based on proprietary criterion). Each profile features an overview of the company / organization, its financial performance (if available), information related to its manufacturing facilities, vector manufacturing technology and an informed future outlook.Tabulated profiles of the other key players headquartered in different regions across the globe (shortlisted based on proprietary criterion). Each profile features an overview of the company, its financial performance (if available), information related to its manufacturing capabilities, and an informed future outlook.An analysis of partnerships and collaborations established in this domain since 2015; it includes details of deals that were / are focused on the manufacturing of vectors, which were analyzed on the basis of year of partnership, type of partnership (manufacturing agreement, product / technology licensing, product development, merger / acqusition, research and development agreement, process development / optimization, service alliance, production asset / facility acquisition, supply agreement and others), scale of operation (preclinical, clinical and commercial), type of vector involved (AAV, adenoviral, lentiviral, retroviral, plasmid and others), region and most active players (in terms of number of partnerships).An analysis of the expansions related to viral vector and non-viral vector manufacturing, which have been undertaken since 2015, based on several parameters, such as year of expansion, type of expansion (new facility / plant establishment, facility expansion, technology installation / expansion, capacity expansion, service expansion and others), type of vector (AAV, adenoviral, lentiviral, retroviral, plasmid and others), application area (gene therapy, cell therapy, vaccine and others) and geographical location of the expansion.An analysis evaluating the potential strategic partners (comparing vector based therapy developers and vector purification product developers) for vector and gene therapy product manufacturers, based on several parameters, such as developer strength, product strength, type of vector, therapeutic area, pipeline strength (preclinical and clinical).An overview of other viral / non-viral gene delivery approaches that are currently being researched for the development of therapies involving genetic modification.An in-depth analysis of viral vector and plasmid DNA manufacturers, featuring three schematic representations, a three dimensional grid analysis, representing the distribution of vector manufacturers (on the basis of type of vector) across various scales of operation and type of manufacturer (in-house operations and contract manufacturing services), a heat map of viral vector and plasmid DNA manufacturers based on the type of vector (AAV, adenoviral vector, lentiviral vector, retroviral vector and plasmid DNA) and type of organization (industry (small, mid-sized and large) and non-industry), and a schematic world map representation, highlighting the headquarters and geographical location of key vector manufacturing hubs.An analysis of the various factors that are likely to influence the pricing of vectors, featuring different models / approaches that may be adopted by product developers / manufacturers in order to decide the prices of proprietary vectors.An estimate of the overall, installed vector manufacturing capacity of industry players based on the information available in the public domain, and insights generated via both secondary and primary research. The analysis also highlights the distribution of the global capacity by company size (small, mid-sized and large), scale of operation (clinical and commercial), type of vector (viral vector and plasmid DNA) and region (North America, Europe, Asia Pacific and the rest of the world).An informed estimate of the annual demand for viral and non-viral vectors, taking into account the marketed gene-based therapies and clinical studies evaluating vector-based therapies; the analysis also takes into consideration various relevant parameters, such as target patient population, dosing frequency and dose strength.A discussion on the factors driving the market and various challenges associated with the vector production process.A qualitative analysis, highlighting the five competitive forces prevalent in this domain, including threats for new entrants, bargaining power of drug developers, bargaining power of vector and gene therapy manufacturers, threats of substitute technologies and rivalry among existing competitors.

One of the key objectives of this report was to evaluate the current market size and the future opportunity associated with the vector and gene therapy manufacturing market, over the coming decade. Based on various parameters, such as the likely increase in number of clinical studies, anticipated growth in target patient population, existing price variations across different types of vectors, and the anticipated success of gene therapy products (considering both approved and late-stage clinical candidates), we have provided an informed estimate of the likely evolution of the market in the short to mid-term and long term, for the period 2022-2035. In order to provide a detailed future outlook, our projections have been segmented on the basis of scale of operation (preclinical, clinical and commercial), type of vector (AAV vector, adenoviral vector, lentiviral vector, retroviral vector, plasmid DNA and others), application area (gene therapy, cell therapy and vaccine), therapeutic area (oncological disorders, rare disorders, neurological disorders, sensory disorders, metabolic disorders, musco-skeletal disorders, blood disorders, immunological diseases, and others) and geographical region (North America, Europe, Asia Pacific, MENA, Latin America and rest of the world). In order to account for future uncertainties and to add robustness to our model, we have provided three forecast scenarios, namely conservative, base and optimistic scenarios, representing different tracks of the industrys growth.

The research, analysis and insights presented in this report are backed by a deep understanding of key insights generated from both secondary and primary research. For the purpose of the study, we invited over 300 stakeholders to participate in a survey to solicit their opinions on upcoming opportunities and challenges that must be considered for a more inclusive growth. The opinions and insights presented in this study were also influenced by discussions held with senior stakeholders in the industry. The report features detailed transcripts of interviews held with the following industry and non-industry players:Menzo Havenga (Chief Executive Officer and President, Batavia Biosciences)Nicole Faust (Chief Executive Officer & Chief Scientific Officer, CEVEC Pharmaceuticals)Cedric Szpirer (Former Executive & Scientific Director, Delphi Genetics)Olivier Boisteau, (Co-Founder / President, Clean Cells), Laurent Ciavatti (Former Business Development Manager, Clean Cells) and Xavier Leclerc (Head of Gene Therapy, Clean Cells)Alain Lamproye (Former President of Biopharma Business Unit, Novasep)Joost van den Berg (Former Director, Amsterdam BioTherapeutics Unit)Bakhos A Tannous (Director, MGH Viral Vector Development Facility, Massachusetts General Hospital)Eduard Ayuso, DVM, PhD (Scientific Director, Translational Vector Core, University of Nantes)Colin Lee Novick (Managing Director, CJ Partners)Semyon Rubinchik (Scientific Director, ACGT)Astrid Brammer (Senior Manager Business Development, Richter-Helm)Marco Schmeer (Project Manager, Plasmid Factory) and Tatjana Buchholz (Former Marketing Manager, Plasmid Factory)Brain M Dattilo (Business Development Manager, Waisman Biomanufacturing)Beatrice Araud (ATMP Key Account Manager, EFS-West Biotherapy)Nicolas Grandchamp (R&D Leader, GEG Tech)Graldine Gurin-Peyrou (Director of Marketing and Technical Support, Polypus Transfection)Naiara Tejados, Head of Marketing and Technology Development, VIVEBiotech)Jeffery Hung (Independent Consultant)

All actual figures have been sourced and analyzed from publicly available information forums and primary research discussions. Financial figures mentioned in this report are in USD, unless otherwise specified.

RESEARCH METHODOLOGYThe data presented in this report has been gathered via secondary and primary research. For all our projects, we conduct interviews with experts in the area (academia, industry, medical practice and other associations) to solicit their opinions on emerging trends in the market. This is primarily useful for us to draw out our own opinion on how the market may evolve across different regions and technology segments. Wherever possible, the available data has been checked for accuracy from multiple sources of information.

The secondary sources of information include:Annual reportsInvestor presentationsSEC filingsIndustry databasesNews releases from company websitesGovernment policy documentsIndustry analysts views

While the focus has been on forecasting the market over the period 2022-2035, the report also provides our independent view on various technological and non-commercial trends emerging in the industry. This opinion is solely based on our knowledge, research and understanding of the relevant market gathered from various secondary and primary sources of information.

KEY QUESTIONS ANSWEREDWho are the leading players (contract service providers and in-house manufacturers) engaged in the development of vectors and gene therapies?Which regions are the current manufacturing hubs for vectors and gene therapies?Which type of vector related technologies are presently offered / being developed by the stakeholders engaged in this domain?Which companies are likely to partner with viral and non-viral vector contract manufacturing service providers?Which partnership models are commonly adopted by stakeholders engaged in this industry?What type of expansion initiatives are being undertaken by players in this domain?What are the various emerging viral and non-viral vectors used by players for the manufacturing of genetically modified therapies?What are the strengths and threats for the stakeholders engaged in this industry?What is the current, global demand for viral and non-viral vector, and gene therapies?How is the current and future market opportunity likely to be distributed across key market segments?

CHAPTER OUTLINES

Chapter 2 is an executive summary of the insights captured in our research. It offers a high-level view on the likely evolution of the vector and gene therapy manufacturing market in the short to mid-term, and long term.

Chapter 3 is a general introduction to the various types of viral and non-viral vectors. It includes a detailed discussion on the design, manufacturing requirements, advantages, limitations and applications of the currently available gene delivery vehicles. The chapter also features the clinical and approved pipeline of genetically modified therapies. Further, it includes a review of the latest trends and innovations in the contemporary vector manufacturing market.

Chapter 4 provides a detailed overview of close to 150 companies, featuring both contract service providers and in-house manufacturers that are actively involved in the production of viral vectors and / or gene therapies utilizing viral vectors. The chapter provides details on the year of establishment, company size, location of headquarters, type of product manufactured (vector and gene therapy / cell therapy / vaccine), location of manufacturing facilities, type of manufacturer (in-house and contract services), scale of operation (preclinical, clinical and commercial), type of vector manufactured (AAV, adenoviral, lentiviral, retroviral, plasmid DNA and others) and application area (gene therapy, cell therapy, vaccine and others).

Chapter 5 provides an overview of close to 70 industry players that are actively involved in the production of plasmid DNA and other non-viral vectors and / or gene therapies utilizing non-viral vectors. The chapter provides details on the the year of establishment, company size, location of headquarters, type of product manufactured (vector and gene therapy / cell therapy / vaccine), location of plasmid DNA manufacturing facilities, type of manufacturer (in-house and contract services), scale of operation (preclinical, clinical and commercial) and application area (gene therapy, cell therapy, vaccine and others).

Chapter 6 provides an overview of close to 90 non-industry players (academia and research institutes) that are actively involved in the production of vectors (both viral and non-viral) and / or gene therapies. The chapter provides details on the year of establishment, type of manufacturer (in-house and contract services), scale of operation (preclinical, clinical and commercial), location of headquarters, type of vector manufactured (AAV, adenoviral, lentiviral, retroviral, plasmid DNA and others) and application area (gene therapy, cell therapy, vaccine and others).

Chapter 7 features an in-depth analysis of the technologies offered / developed by the companies engaged in this domain, based on the type of technology (viral vector and non-viral vector related platform), purpose of technology (vector manufacturing, gene delivery, product manufacturing, transduction / transfection, vector packaging and other), scale of operation (preclinical, clinical and commerical), type of vector involved (AAV, adenoviral, lentiviral, retroviral, non-viral and other viral vectors), application area (gene therapy, cell therapy, vaccine and others) and leading technology providers.

Chapter 8 presents a detailed competitiveness analysis of vector manufacturers across key geographical areas, featuring a four-dimensional bubble representation, taking into consideration supplier strength (based on its experience in this field), manufacturing strength (type of product manufactured, number of manufacturing facilities and number of application area), service strength (scale of operation, number of vectors manufactured and geographical reach) and company size (small, mid-sized and large).

Chapter 9 features detailed profiles of some of the key players that have the capability to manufacture viral vectors / plasmid DNA in North America. Each profile presents a brief overview of the company, its financial information (if available), details on vector manufacturing facilities, manufacturing experience and an informed future outlook.

Chapter 10 features detailed profiles of some of the key players that have the capability to manufacture viral vectors / plasmid DNA in Europe. Each profile presents a brief overview of the company, its financial information (if available), details on vector manufacturing facilities, manufacturing experience and an informed future outlook.

Chapter 11 features detailed profiles of some of the key players that have the capability to manufacture viral vectors / plasmid DNA in Asia-Pacific. Each profile presents a brief overview of the company, its financial information (if available), details on vector manufacturing facilities, manufacturing experience and an informed future outlook.

Chapter 12 features tabulated profiles of the other key players that have the capability to manufacture viral vectors / plasmid DNA. Each profile features an overview of the company, its financial performance (if available), information related to its manufacturing capabilities, and an informed future outlook.

Chapter 13 features in-depth analysis and discussion of the various partnerships inked between the players in this market, during the period, 2015-2022, covering analysis based on parameters such as year of partnership, type of partnership(manufacturing agreement, product / technology licensing, product development, merger / acquisition, research and development agreement, process development / optimization, service alliance, production asset / facility acquisition, supply agreement and others), scale of operation (preclinical, clinical and commercial) and type of vector (AAV, adenoviral, lentiviral, retroviral, plasmid and others) most active players (in terms of number of partnerships).

Chapter 14 features an elaborate discussion and analysis of the various expansions that have been undertaken, since 2015. Further, the expansion activities in this domain have been analyzed on the basis of year of expansion, type of expansion (new facility / plant establishment, facility expansion, technology installation / expansion, capacity expansion, service expansion and others), geographical location of the facility, type of vector (AAV, adenoviral, lentiviral, retroviral, plasmid and others) and application area (gene therapy, cell therapy, vaccine and others).

Chapter 15 highlights potential strategic partners (vector based therapy developers and vector purification product developers) for vector and gene therapy product manufacturers, based on several parameters, such as developer strength, product strength, type of vector, therapeutic area, pipeline strength (clinical and preclinical). The analysis aims to provide the necessary inputs to the product developers, enabling them to make the right decisions to collaborate with industry stakeholders with relatively more initiatives in the domain.

Chapter 16 provides detailed information on other viral / non-viral vectors. These include alphavirus vectors, Bifidobacterium longum vectors, Listeria monocytogenes vectors, myxoma virus based vectors, Sendai virus based vectors, self-complementary vectors (improved versions of AAV), minicircle DNA and Sleeping Beauty transposon vectors (non-viral gene delivery approach) and chimeric vectors, that are currently being utilized by pharmaceutical players to develop gene therapies, T-cell therapies and certain vaccines, as well. This chapter presents overview on all the aforementioned types of vectors, along with examples of companies that use them in their proprietary products. It also includes examples of companies that are utilizing specific technology platforms for the development / manufacturing of some of these novel vectors.

Chapter 17 presents a collection of key insights derived from the study. It includes a grid analysis, highlighting the distribution of viral vectors and plasmid DNA manufacturers on the basis of their scale of operation and type of manufacturer (fulfilling in-house requirement / contract service provider). In addition, it consists of a heat map of viral vector and plasmid DNA manufacturers based on the type of vector (AAV, adenoviral vector, lentiviral vector, retroviral vector and plasmid DNA) and type of organization (industry (small, mid-sized and large) and non-industry). The chapter also consists of six world map representations of manufacturers of viral / non-viral vectors (AAV, adenoviral, lentiviral, retroviral vectors, and plasmid DNA), depicting the most active geographies in terms of the presence of the organizations. Furthermore, we have provided a schematic world map representation to highlight the geographical locations of key vector manufacturing hubs across different continents.

Chapter 18 highlights our views on the various factors that may be taken into consideration while pricing viral vectors / plasmid DNA. It features discussions on different pricing models / approaches that manufacturers may choose to adopt to decide the prices of their proprietary products.Chapter 19 features an informed analysis of the overall installed capacity of the vectors and gene therapy manufacturers. The analysis is based on meticulously collected data (via both secondary and primary research) on reported capacities of various small, mid-sized and large companies, distributed across their respective facilities. The results of this analysis were used to establish an informed opinion on the vector production capabilities of the organizations by company size (small, mid-sized and large), scale of operation (clinical and commercial), type of vector (viral vector and plasmid DNA) and region (North America, Europe, Asia Pacific and the rest of the world).

Chapter 20 features an informed estimate of the annual demand for viral and non-viral vectors, taking into account the marketed gene-based therapies and clinical studies evaluating vector-based therapies. This section offers an opinion on the required scale of supply (in terms of vector manufacturing services) in this market. For the purpose of estimating the current clinical demand, we considered the active clinical studies of different types of vector-based therapies that have been registered till date. The data was analyzed on the basis of various parameters, such as number of annual clinical doses, trial location, and the enrolled patient population across different geographies. Further, in order to estimate the commercial demand, we considered the marketed vector-based therapies, based on various parameters, such as target patient population, dosing frequency and dose strength.

Chapter 21 presents a comprehensive market forecast analysis, highlighting the likely growth of vector and gene therapy manufacturing market till the year 2030. We have segmented the financial opportunity on the basis of type of vector (AAV vector, adenoviral vector, lentiviral vector, retroviral vector, plasmid DNA and others), application area (gene therapy, cell therapy and vaccine), therapeutic area (oncological disorders, rare disorders, neurological disorders, sensory disorders, metabolic disorders, musco-skeletal disorders, blood disorders, immunological diseases, and others), scale of operation (preclinical, clinical and commercial) and geography (North America, Europe, Asia Pacific, MENA, Latin America and rest of the world). Due to the uncertain nature of the market, we have presented three different growth tracks outlined as the conservative, base and optimistic scenarios.

Chapter 22 highlights the qualitative analysis on the five competitive forces prevalent in this domain, including threats for new entrants, bargaining power of drug developers, bargaining power of vector and gene therapy manufacturers, threats of substitute technologies and rivalry among existing competitors.

Chapter 23 provides details on the various factors associated with popular viral vectors and plasmid DNA that act as market drivers and the various challenges associated with the production process. This information has been validated by soliciting the opinions of several industry stakeholders active in this domain.

Chapter 24 presents insights from the survey conducted on over 300 stakeholders involved in the development of different types of gene therapy vectors. The participants, who were primarily Director / CXO level representatives of their respective companies, helped us develop a deeper understanding on the nature of their services and the associated commercial potential.

Chapter 25 summarizes the entire report, highlighting various facts related to contemporary market trend and the likely evolution of the viral vector, non-viral vector and gene therapy manufacturing market.

Chapter 26 is a collection of transcripts of the interviews conducted with representatives from renowned organizations that are engaged in the vector and gene therapy manufacturing domain. In this study, we spoke to Menzo Havenga (Chief Executive Officer and President, Batavia Biosciences), Nicole Faust (Chief Executive Officer & Chief Scientific Officer, CEVEC Pharmaceuticals), Cedric Szpirer (Former Executive & Scientific Director, Delphi Genetics), Olivier Boisteau, (Co-Founder / President, Clean Cells), Laurent Ciavatti (Former Business Development Manager, Clean Cells) and Xavier Leclerc (Head of Gene Therapy, Clean Cells), Alain Lamproye (Former President of Biopharma Business Unit, Novasep), Joost van den Berg (Former Director, Amsterdam BioTherapeutics Unit), Bakhos A Tannous (Director, MGH Viral Vector Development Facility, Massachusetts General Hospital), Eduard Ayuso, DVM, PhD (Scientific Director, Translational Vector Core, University of Nantes), Colin Lee Novick (Managing Director, CJ Partners), Semyon Rubinchik (Scientific Director, ACGT), Astrid Brammer (Senior Manager Business Development, Richter-Helm), Marco Schmeer (Project Manager, Plasmid Factory) and Tatjana Buchholz (Former Marketing Manager, Plasmid Factory), Brain M Dattilo (Business Development Manager, Waisman Biomanufacturing), Beatrice Araud (ATMP Key Account Manager, EFS-West Biotherapy), Nicolas Grandchamp (R&D Leader, GEG Tech), Graldine Gurin-Peyrou (Director of Marketing and Technical Support, Polypus Transfection), Naiara Tejados, Head of Marketing and Technology Development, VIVEBiotech) and Jeffery Hung (Independent Consultant)

Chapter 27 is an appendix, which provides tabulated data and numbers for all the figures in the report.

Chapter 28 is an appendix that provides the list of companies and organizations that have been mentioned in the report.Read the full report: https://www.reportlinker.com/p06323417/?utm_source=GNW

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Viral Vector Manufacturing, Non-Viral Vector Manufacturing and Gene Therapy Manufacturing Market by Scale of Operation, Type of Vector, Application...

By the end of March, Vertex Pharmaceuticals and CRISPR Therapeutics expect to have submitted a U.S. approval application for a gene editing medicine designed to treat two rare blood disorders.

On Tuesday, the companies said the Food and Drug Administration is allowing a so-called rolling review of their medicine, named exa-cel, for the treatment of sickle cell disease and beta thalassemia. Filing is slated to begin in November, with a completed application anticipated some time in the first quarter of next year. In Europe, where Vertex and CRISPR are also seeking approval, the companies said theyre on track to file by the end of this year.

If approved, exa-cel would become the first marketed therapy based on the CRISPR gene editing technology that won a Nobel Prize in 2020. Data generated in clinical studies have so far shown that, for most patients, a one-time treatment with exa-cel significantly alleviates the symptoms and burdens of sickle cell and beta thalassemia.

We continue to work with urgency to bring forward the first CRISPR therapy for a genetic disease, and one that holds potential to transform the lives of patients, said Nia Tatsis, Vertexs chief regulatory and quality officer, in a statement.

Vertex previously aimed to submit a full application by the end of 2022, wrote Brian Abrahams, an analyst at the investment firm RBC Capital Markets, in a note to clients.Still, Abrahams and his team wouldnt expect a few months of difference in expected filing time to be material.

More concerning, according to the RBC team, is the potential sales outlook for exa-cel.

Several companies, including deep-pocked players like Pfizer, Novartis and Novo Nordisk, are trying to develop new medicines for sickle cell and beta thalassemia. And just last month, Massachusetts-based Bluebird bio secured FDA approval of a gene therapy another one-time, long-lasting treatment for patients with severe beta thalassemia who require blood transfusions. Bluebird is developing a gene therapy for sickle cell, too.

Additionally, the way exa-cel is administered could affect how many patients seek it out.

The medicine is made with a patients own stem cells, which are engineered and then implanted back into the bone marrow. The process requires patients be conditioned with busulfan, a chemotherapy-based regimen that can be difficult to tolerate. For example, one patient in the exa-cel clinical trial experienced bleeding in the brain that researchers attributed to this regimen.

CRISPR has said its exploring alternative conditioning procedures that dont involve chemotherapy. Even so, some analysts remain skeptical. Luca Issi, an RBC analyst who covers Beam Therapeutics, another company developing a gene-editing treatment for sickle cell, believes the commercial prospects for Beams program would be capped by its use of busulfan conditioning.

We remain cautious on exa-cel's ultimate commercial opportunity given our prior [conversations with doctors and patients], at least not until the much longer term once less toxic pre-conditioning regimens can be deployed, Abrahams wrote.

Vertex, meanwhile, has appeared more confident in exa-cels sales potential. Last year, the company paid CRISPR $900 million to amend their partnership so Vertex receives a greater portion of the profits should exa-cel come to market.

Read more:
Vertex given green light to seek US approval of CRISPR-based therapy - BioPharma Dive

Tenaya Therapeutics, Inc.

Encore Presentation of Lead Gene Therapy TN-201 Preclinical Data to be Featured in Late-Breaking Trials Session

SOUTH SAN FRANCISCO, Calif., Sept. 29, 2022 (GLOBE NEWSWIRE) -- Tenaya Therapeutics, Inc. (NASDAQ: TNYA), a clinical-stage biotechnology company with a mission to discover, develop and deliver potentially curative therapies that address the underlying causes of heart disease, announced today that it is scheduled to participate in the Hypertrophic Cardiomyopathy Medical Societys (HCMS) inaugural 2022 Scientific Sessions taking place September 30, 2022, virtually and in National Harbor, MD.

Milind Desai, M.D., MBA, Director of the Center for Hypertrophic Cardiomyopathy and Director of Clinical Operations, Heart, Vascular & Thoracic Institute at Cleveland Clinicwill present preclinical data for Tenayas TN-201, a gene therapy candidate intended to correct the underlying genetic cause of HCM, MYBPC3 gene mutations. Variants in the MYBPC3 gene are the most common genetic cause of HCM, believed to contribute to approximately 20 percent of all HCM cases. Whit Tingley, M.D., Ph.D., Tenayas Chief Medical Officer, will join an industry panel to discuss advances in genetic therapies and its potential in individuals with HCM.

Details of Tenayas participation are as follows:

September 30, 2022Time: 10:50 a.m. 11:10 a.m. ETSession: Late-Breaking TrialsTitle: Early Breaking Trial 3 Gene Therapy Candidate for Hypertrophic Cardiomyopathy Patients with MYBPC3 MutationPresenter: Dr. Milind Desai, Cleveland Clinic

Time: 12:15 p.m. 12:55 p.m. ETSession: Industry RoundtableSpeaker: Whit Tingley, M.D., Ph.D., Tenaya Therapeutics

The HCMS Sessions are intended to highlight the history, major developments and emerging concepts in hypertrophic cardiomyopathy (HCM), including learning about genetic forms of HCM and emerging treatments. A copy of the presentation will be posted to Tenayas website. To view full event programming, please visit the HCMS website.

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About TN-201 for MYBPC3-associated Hypertrophic CardiomyopathyTN-201 is an adeno-associated virus-based gene therapy being developed to treat hypertrophic cardiomyopathy (HCM) due to disease-causing variants in the Myosin Binding Protein C3 (MYBPC3) gene. HCM is a chronic, progressive condition in which the walls of the left ventricle become significantly thickened, leading to abnormal heart rhythms, cardiac dysfunction, heart failure and increased risk of sudden cardiac death, accompanied by symptoms such as shortness of breath, fainting and palpitations. Variants in MYBPC3 are the most common genetic cause of HCM, estimated to represent approximately 20 percent of the overall HCM population and to affect approximately 115,000 patients in the United States alone. In preclinical studies, following a one-time injection of TN-201 in a severely diseased knock-out model of MYBPC3-associated HCM, a reversal of cardiac dysfunction and improvement in survival was observed. Tenaya plans to submit an Investigational New Drug application for TN-201 to the U.S. Food and Drug Administration in the second half of this year.

AboutTenaya TherapeuticsTenaya Therapeuticsis a clinical-stage biotechnology company committed to a bold mission: to discover, develop and deliver curative therapies that address the underlying drivers of heart disease. Founded by leading cardiovascular scientists fromGladstone Institutesand theUniversity of Texas Southwestern Medical Center, Tenaya is developing therapies for rare genetic cardiovascular disorders as well as for more prevalent heart conditions through three distinct but interrelated product platforms: Gene Therapy, Cellular Regeneration and Precision Medicine. For more information, visitwww.tenayatherapeutics.com.

InvestorsMichelle CorralTenaya TherapeuticsIR@tenayathera.com

MediaWendy RyanTenBridge Communicationswendy@tenbridgecommunications.com

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Tenaya Therapeutics to Participate in Inaugural Hypertrophic Cardiomyopathy Medical Societys 2022 Scientific Sessions - Yahoo Finance

Introduction

Huntingtons disease (HD) is an autosomal dominant neurodegenerative disorder with an estimated prevalence of up to 9 per 100,000 in the USA, Canada, Oceania, and Western Europe.1,2 HD is caused by a CAG (cytosine, adenine, and guanine) repeat expansion in exon 1 of the Huntingtin (HTT) gene, resulting in the translation of a mutant Huntingtin protein harboring a toxic polyglutamine (polyQ) stretch at its amino (N) terminus. Gene carriers with repeats between 36 and 39 CAG show incomplete penetrance, while repeats of 40 and more triplets lead to fully penetrant disease. The age of onset is inversely correlated with the CAG repeat length, with an average age of onset of 3544 years. HD is characterized by motor, cognitive and psychiatric symptoms and is ultimately fatal, with a median survival of 1518 years after onset. About 510% of HD patients show disease onset before 20 years of age, in which case it is called juvenile HD. Juvenile HD has a different clinical presentation compared to adult onset HD, characterized by symptoms such as severe mental retardation, speech and language delay, as well as more pronounced motor and cerebellar symptoms and overall more rapid disease progression.3

Apart from the inherited CAG length, several genetic modifiers have been identified that are associated with age of onset. Many of these modifiers point towards an important role for somatic instability: the process in which the CAG repeat within cells expands over time. Within the HTT locus, a strong genetic modifier is whether or not a CAA (cytosine, adenine, and adenine) interruption is present at the 3 end of the CAG repeat. Similar to CAG triplets, CAA encodes for glutamine, thus resulting in the same polyQ stretch. Nonetheless, alleles that lack this CAA interruption were found to be more prone to somatic expansion and showed decreased age of onset, while the presence of an additional CAA interruption was found to delay both somatic expansion and age of onset.4,5 Moreover, many of the identified trans-acting genetic modifiers, such as FANCD2 And FANCI Associated Nuclease 1 (FAN1) and MutL Homolog 1 (MLH1), are involved in DNA mismatch repair and influence somatic instability of the CAG repeat.5,6

Although HD was initially thought to be mainly a protein toxic gain-of-function disorder, it is likely that protein loss-of-function also plays a role, as reviewed elsewhere,710 and there is increasing evidence for the involvement of other disease mechanisms, such as repeat-associated non-AUG dependent (RAN) translation and RNA toxic gain-of-function, also reviewed previously.1113 Still, little is known regarding the relative contribution of each of these pathogenic mechanisms to the disease (Figure 1).

Figure 1 Schematic overview of the molecular pathogenesis of HD.

HTT is known to be essential for embryonic development, as demonstrated by the fact that knockout mice are embryonically lethal, and also appears to play a role in later stages of development and life, as reviewed by Kaemmerer and Grondin.10 There is, however, no clear consensus on the level of wild type HTT (wtHTT) that is required for its normal function, as this is likely to depend on many factors, including age and tissue/brain region. wtHTT is involved in many important cellular processes, including endocytosis and vesicular trafficking, cell division, autophagy and transcriptional regulation (reviewed by Saudou and Humbert)9 which may all be impacted by a loss of wtHTT function in HD.

Compelling evidence for the involvement of RNA-mediated toxicity was provided by Sun et al, who found that even in the absence of translation, there was still repeat-length dependent toxicity of 5 HTT mRNA as well as full-length HTT.14 RNA toxic gain-of-function is caused by the interaction between RNA-binding proteins (RBPs), such as Muscleblind like splicing regulator 1 (MBNL1) and Pre-mRNA processing factor 8 (PRPF8), and the secondary structure formed by the expanded CAG repeat in the mRNA, affecting the splicing of a range of transcripts.15,16 This interaction appears to be dependent on the purity of the CAG repeat (ie, the absence of CAA interruptions), as Mbnl1 was found to be recruited to nuclear foci in the novel BAC-CAG mouse model, which has an uninterrupted repeat, but not in the BACHD model, which harbors an interrupted repeat.17

Finally, the presence of the expanded CAG repeat has also been shown to induce repeat-associated non-AUG dependent (RAN) translation, which leads to the production of homopolymers other than polyQ that may also negatively impact cell function. RAN translation products have been detected in the affected brain regions of patients, as well as in N171-82Q mice and a C. elegans model.18,19 However, the actual contribution of RAN translation products to HD is not clear, as, for example, no RAN toxicity was observed in HD140Q knock-in mice.20

The expanded polyQ-containing mutant HTT (mHTT) protein has been shown to interact aberrantly with a variety of proteins, including transcriptional regulators such as RNA polymerase II subunit A (POLR2A), Tumor protein p53, Mouse double minute 2 (MDM2), CREB-binding protein (CBP) and Heat shock protein 70 (HSP70), cell cycle regulators like Ras homolog enriched in brain (Rheb) and mammalian target of rapamycin (mTOR), and cytoskeleton proteins such as actin and neurofilament light (NF-L). These aberrant interactions result in a complex and widespread molecular pathology, affecting many essential processes in the cell, including DNA damage repair, transcriptional regulation, mitochondrial function and apoptosis.2125 Importantly, premature polyadenylation of the pre-mRNA as well as proteolytic cleavage of HTT protein lead to the production of a variety of HTT fragments, and there is ample evidence that such fragments, especially the short N-terminal species, are more toxic than the full-length mHTT protein.2635 In order to make tailored therapeutics towards the short toxic fragments, a good understanding of the mechanisms leading to their formation is needed. In this review, we therefore focus on how toxic N-terminal HTT protein species are produced and how they are linked to toxicity, as well as on therapeutic strategies that are capable of reducing these fragments.

N-terminal HTT protein fragments are mainly produced through two distinct processes: proteolytic cleavage and premature polyadenylation (see Figure 2 and Table 1).

Table 1 Overview of Proteolytic Cleavage Sites

Figure 2 Schematic overview of production of N-terminal HTT protein. (A) Regular splicing, overview of the resulting mRNA and full-length protein and the identified proteolytic cleavage sites. (B) Alternative splicing and premature polyadenylation and resulting transcript. (C) Resulting protein species and propensity for nuclear entry, aggregation and toxicity.

The group of Michael Hayden first showed that HTT could be cleaved proteolytically by apopain (caspase-3) in a repeat-length dependent manner.36 This was confirmed in a follow-up study, in which they mapped one of the caspase-3 cleavage sites to D513 and another site C-terminally of amino acid (aa) 548. Furthermore, two caspase-1 cleavage sites were identified in the first 548 aa. In contrast to their previous work with truncated HTT, the authors found no repeat-length dependence of cleavage efficiency of full-length HTT.37 In a third study, the authors were able to map the second caspase-3 cleavage site to D552, and further identified a caspase-6 cleavage site at D586.38 More recently, Martin et al recently identified yet another caspase cleavage site at D572, which was shown to be cleaved by caspase-1 and caspase-2.39

Both full-length and N-terminal caspase-cleavage products of HTT were found to be substrates for cleavage by calpains.4042 Four calpain cleavage sites have been mapped, at aa 437, 465/469 and 536/54041 and between aa 63111,42 calpain cleavage efficiency appears to be positively correlated with repeat length.41,42 Furthermore, it was shown that calpain levels, and in particular the active form, were increased in the caudate of HD patients compared to controls.41

Next to caspase and calpain generated fragments, various other cleaved HTT products have been described. Lunkes et al identified two N-terminal HTT fragments, cp-A and cp-B, which appeared to be generated in transfected NG108 cells through cleavage by aspartic endopeptidases. The C-terminus of HTT cp-A fragment was mapped between aa 104114. N-terminal fragments with the same immunogenic properties were identified in nuclear inclusions in post mortem frontal cortex of HD patients.43

Similarly, Schilling et al identified an N-terminal fragment ending between aa 90115 in post mortem tissues from HD patients and N171-82Q mice, as well as in transfected HEK293 cells.44 Further investigation in a HEK293 cell model revealed that short, HTT cp-B-like fragments were efficiently processed to HTT cp-A-like fragments, while longer HTT fragments proved to be inefficient substrates. The C-terminus of the HTT cp-A-like fragments was mapped between aa 105 and 115124. Although similar in size to the fragment described by Lunkes et al, inhibition of aspartyl proteases did not affect the formation of the cp-A-like fragment, and the authors were unable to identify any protease that generates these HTT cp-A-like fragments, suggesting that i) the fragments are not the same or ii) that the cp-A-like fragment described by Schilling et al is the same fragment but generated by a novel protease, which may be cell-type dependent.45 Ratovitski et al identified two N-terminal fragments (HTT cp-1 and cp-2) in PC12 and HEK293 cells expressing full-length HTT with 21Q or 126153Q or a truncated N1212 HTT fragment with 15Q or 138Q.46 These fragments were similar in size to the previously described HTT cp-A and cp-B fragments but were not affected by inhibition of aspartic endopeptidases. In addition, they were not affected by deletion of aa 105114. In combination with the epitope mapping, this narrowed the C-terminus of the HTT cp-1 fragment down to between aa 90 and 105, shorter than the cp-A and cp-A-like fragments described by Lunkes et al43 and Schilling et al44,45 Based on the absence of identified proteases and on the fragment length, we speculate that the generation of these fragments could involve aberrant splicing (see Aberrant Splicing and Premature Polyadenylation), although this would require further investigation.

Finally, Landles et al showed fourteen different N-terminal HTT protein isoforms (fragments 114) in brain tissue from HdhQ150 KI mice, the three shortest of which (fragments 1214) were specific to mHTT.33 Some of these fragments could be linked to specific proteolytic cleavage events: fragment 7 terminated at a novel calpain cleavage site between aa 510654, fragment 8 appeared to correspond to the D586 caspase-6 cleavage product, fragment 9 was likely produced by cleavage at calpain site 536 and fragment 10 by caspase cleavage at D513. Lastly, fragment 13 was determined to correspond to HTT-ex1.

In summary, many different proteases have been found to act on mHTT and wtHTT, generating N-terminal and C-terminal HTT fragments. The availability of antibodies that can recognize these fragments, as well as the possibility to specifically inhibit certain proteases, have allowed mapping of various fragments, albeit with variable resolution. Nonetheless, for multiple fragments, the mechanisms of production remain to be identified.

Besides proteolytic cleavage, there are other mechanisms that lead to the generation of toxic N-terminal mHTT fragments. Sathasivam et al showed that incomplete splicing of intron 1 leads to the production of a short premature polyadenylated HTT-ex1 transcript in various HD mouse models and that this HTT-ex1 can be translated into a 90 aa N-terminal HTT-ex1 protein (based on 23Q). HTT-ex1 transcript was also found to be expressed in HD patient fibroblasts and cortex.47 In a follow-up study, Neueder et al confirmed that the HTT-ex1 transcript can be detected in patient-derived fibroblasts, as well as HD patient cerebellum, sensory motor cortex and hippocampus, with the highest expression levels measured in juvenile HD patient tissues.48 The HTT-ex1 transcript has also been detected by RNA-sequencing in various HD mouse models, including BACHD, BAC-CAG and HdhQ111.17 Both in vitro and in patient-derived tissues, the production of the HTT-ex1 transcript appears to be positively correlated with CAG repeat length, showing much higher expression in cells and tissues derived from juvenile HD patients.48,49

The current hypothesis is that HTT-ex1 formation is influenced by a combination of sequestration of spliceosome components such as U1 snRNP at the CAG repeat, leading to less efficient splicing of exon 1 to exon 2, and a reduced transcription rate, which leads to longer exposure of the cryptic polyA site in intron 1. Although the Bates group initially found evidence for the involvement of Serine and Arginine Rich Splicing Factor 6 (SRSF6) in HTT-ex1 formation,47,49 they later found that the silencing of Srsf6 in HD mouse models did not affect HTT-ex1 formation.50 It has therefore been hypothesized that multiple RNA-binding proteins may be involved in the missplicing of HTT-ex1.12 Regardless of the exact mechanisms involved, aberrant mHTT splicing is CAG repeat length dependent, suggesting that HTT-ex1 formation and associated toxicity would increase as somatic instability progresses in HD48 and that interventions targeting repeat expansion and HTT-ex1 may have therapeutic advantage.

Consistently accumulating evidence indicates that small N-terminal fragments containing extended polyQ tracts significantly contribute mHTT cellular mislocalization, aggregation and toxicity. Initial studies by the Ross group showed that transfection of N2a or HEK293 cells with full-length HTT with either 23Q or 82Q, or of truncated HTT N171-18Q or N63-18Q resulted in a diffuse cytoplasmic localization of the protein. In contrast, transfection with N171-82Q or N63-82Q led to more punctate labeling in both cytoplasm and nucleus, with the short N63-82Q construct showing the most prominent nuclear localization.51 The Hayden group found similar results, showing that N-terminal fragments of 427, 548 or more aa formed mainly perinuclear aggregates, while fragments up to 224 aa showed both cytoplasmic and nuclear aggregates. Furthermore, they found that pathogenicity depended both on repeat length and on fragment size.26,27

Barbaro et al found that, in Drosophila, shorter N-terminal fragments were more toxic and more prone to aggregate, with HTT-ex1 being by far the most toxic species.28 In mice, the R6/2 model that expresses only HTT-ex1 is by far the most swiftly progressing HD mouse model,52,53 while conditional suppression of HTT-ex1 has been shown to be neuroprotective.54 Recent in vitro studies by the Lashuel group confirm these results and further extend the findings by showing that the polyQ and Nt17 domains of HTT-ex1 synergistically modulate the aggregation propensity of HTT-ex1, with a key role of the Nt17 domain in regulating HTT-ex1 aggregation dynamics and subcellular localization and toxicity.34

There is conflicting evidence with regard to the pathogenicity of nuclear and cytoplasmic mHTT. Some groups have reported evidence that nuclear localization is required for toxicity. For example, the Greenberg group showed that adding a nuclear export signal to a N171 HTT fragment blocked its toxicity in transfected striatal neurons.55 In contrast, the Hayden group reported that neither the addition of a nuclear localization signal to a N548 HTT fragment nor the addition of a nuclear export signal to a N151 fragment altered the toxicity of those fragments, suggesting that both the nucleus and the cytoplasm are sites of HD toxicity.56 Trushina et al found that nuclear entry of mHTT only occurred after commitment of a cell to cell death. Therefore, the authors argue that nuclear mHTT localization may not be the primary event leading to toxicity.57

Intranuclear and neuropil aggregates have been observed in most HD animal models,17,30,31,5863 and the presence of aggregates containing N-terminal HTT fragments has also been confirmed in patient brains by multiple groups.40,64,65 However, various groups have shown that it is not the insoluble aggregates or inclusion bodies, but rather the soluble oligomers that are the more toxic species.6669 In fact, some groups have found evidence that the formation of intranuclear inclusions may be protective,55,70,71 as reviewed by Arrasate and Finkbeiner.72 Mechanistically, this may be explained by the fact that soluble mHTT-ex1 oligomers have more aberrant protein interactions than insoluble aggregates and inclusions.73 Importantly, the length of N-terminal protein species and the associated sequence context, as well as post-translational modifications, also appear to play an important role in the aggregation process.35,74,75 For more in-depth reviews on the role of post-translational modifications, we redirect elsewhere.76,77

Various approaches have been investigated to therapeutically lower the expression or reduce the toxicity of the mutant HTT protein. The proteolytic cleavage pathway can be targeted to reduce the formation of N-terminal mHTT protein species. Furthermore, the N-terminal part of the protein can be targeted to reduce aggregation and/or increase clearance of mHTT. Finally, mHTT can be targeted at the transcript or gene level. Here, we will focus on approaches that are able to target not only full-length HTT but also HTT-ex1 and other N-terminal mHTT species, considering their potential therapeutic advantage (see Table 2).

Table 2 Overview of Studies Targeting HTT Protein

Caspase inhibition has been shown to reduce the proteolytic cleavage of mHTT and to improve the HD phenotype in BACHD78 and HdhQ111 mice.79 These results are backed up by earlier studies, where mutation of caspase-6 cleavage sites slowed down disease progression in YAC128 mice.80 However, it is not clear to what extent the protective effects are due specifically to the reduction of N-terminal mHTT species, rather than a general protective effect of caspase inhibition, as caspase inhibition was also protective in R6/2 and malonate models of HD, which do not express caspase-cleavable mHTT.8183

Using a different approach, Evers et al showed that removal of the caspase-6 cleavage site by antisense oligonucleotide (ASO)-mediated skipping of (part of) exon 12 led to reduced levels of the N568 fragment in vitro and in vivo in wild type and YAC128 mice.84,85 Except for the absence of astrogliosis, no data are available regarding phenotypic effects of this ASO treatment.

None of these approaches have yet successfully been translated into the clinic, and although all may potentially decrease the formation of toxic mHTT fragments and have the potential of allele-specificity, mechanisms of RNA-associated toxicity would not be addressed.

Aptamers are single-stranded oligonucleotides that, through their tertiary structure, can interact with target molecules such as proteins. The Roy lab identified aptamers that bind specifically to mHTT with 51 or 103Q but not wtHTT with 20Q.86,87 The selected aptamers were shown to inhibit aggregation of recombinant mHTT-ex1 in cell-free assays and in yeast, as well as reducing oxidative stress and mitochondrial dysfunction.86 To our knowledge, this approach has not yet been tested in vivo.

Various antibodies have been expressed intracellularly as intrabodies to target the N-terminus of HTT. In vivo, such intrabodies are delivered using viral vectors. An excellent review on the use of intrabodies in various neurodegenerative diseases was written by Messer and Butler.88

Two groups of intrabodies have been tested most extensively (see Figure 3): those that bind to the N-terminus of HTT (VL12.3, scFv-C4) and those that recognize the proline-rich regions (PRRs) in HTT-ex1 (MW7, Happ1, Happ3, INT41). In addition, there is some literature about polyQ-binding intrabodies (MW1, MW2) and a more C-terminal intrabody derived from EM48 (scFv-EM48).

Figure 3 Anti-HTT Exon 1 intrabodies. (A) Antigens used to select the published anti-HTT intrabodies. (B) Specific binding identified by crystallography for scFvC4 and VL12.3.

Notes: Reproduced from Messer A, Butler DC. Optimizing intracellular antibodies (intrabodies/nanobodies) to treat neurodegenerative disorders. Neurobiol Dis. 2020;134(October 2019):104619. doi: 10.1016/j.nbd.2019.104619 under Creative Commons BY-NC-ND 4.0.88

Southwell et al showed that intrabodies that bind to the PRR, ie, MW7, Happ1 and Happ3, increase the turnover of mHTT-ex1 overexpressed in vitro. VL12.3, an intrabody that binds to the N-terminal 17 aa of HTT, did not affect turnover, but did increase the nuclear localization of mHTT-ex1.90 In vivo, the PRR-binding Happ1 was shown to be beneficial in five different HD mouse models. In contrast, VL12.3, while effective in a lentiviral HD model, was ineffective in YAC128 mice and had a detrimental effect in R6/2 mice.91 The authors later showed that the increased turnover mediated by the PRR-binding intrabodies is dependent on a calpain-chaperone-mediated autophagy-dependent mechanism and that this process is blocked by VL12.3,92 explaining the detrimental effects of VL12.3.

Although scFv-C4 also binds to the N-terminus of HTT,93 its predominant cytoplasmic localization appears to protect from the detrimental effects observed for VL12.3.89 The scFv-C4 intrabody was shown to have beneficial effects in various HD models, including in vitro models, Drosophila and different mouse models.9498

Two additional intrabodies have been investigated: scFv-EM48 and INT41. Like Happ1, scFv-EM48, which binds just C-terminally to the second PRR, was shown to increase turnover of mHTT, and improved motor function of N171-82Q mice.99 INT41, an intrabody that recognizes the same epitope as Happ1, but which has enhanced cytoplasmic solubility, was shown to improve cognitive function in female R6/2 mice.100

In addition to the increased turnover induced by some of the intrabodies, the endogenous cellular machinery can be harnessed specifically to target proteins for degradation, using engineered proteins, peptides or small molecules. These can direct the protein of interest to the ubiquitin proteasome system, the autophagy-lysosomal pathway or chaperone-mediated autophagy. These approaches and their specific application in the context of HD have been extensively reviewed by Jarosiska and Rdiger.101

Two such approaches specifically target the polyQ region. Bauer et al engineered a fusion molecule consisting of two copies of a polyQ-binding peptide (QBP1) and heat shock-cognate protein 70 (HSC70)-binding motifs to induce chaperone-mediated autophagy.102 Clift et al co-expressed a polyQ-binding antibody (3B5H10) with TRIM21 in an approach that they call Trim-Away, to target mHTT for proteasomal degradation.103 Additionally, Butler et al produced a fusion protein consisting of the scFv-C4 intrabody and a PEST motif to enhance proteasomal degradation of HTT-ex1.104

Several endogenous proteins have been described to enhance the turnover of mHTT, including Praja1 ubiquitin ligase,105 TBK1106 and Blm10/PA200.107 Induction or overexpression of such proteins may represent a therapeutic strategy, although, so far, this notion is only supported by experiments in cellular, Drosophila, and C. elegans models. Additionally, specificity for mHTT has not been shown for any of these three proteins.

Finally, a small molecule that can bind to mHTT-ex1, called GLYN122, has been identified recently. GLYN122 was shown to reduce mHTT-ex1 aggregation in PC12 cells, as well as reducing mHTT in cortex and striatum of R6/2 mice after intraperitoneal injection.108

Next to targeting the pathogenic protein species itself, the production of such proteins can also be inhibited by targeting the HTT mRNA. Many different approaches have been tested to this effect, including ASOs, siRNAs, shRNAs and miRNAs (Table 3). Again, we only focus on those strategies that target HTT-ex1. Broadly speaking, the HTT-ex1 mRNA targeting approaches can be divided into those that target the expanded CAG repeat, and those that target other regions of HTT-ex1. In addition, some other approaches have been described.

Table 3 Overview of Studies That Evaluated Therapeutic Approaches Targeting HTT at the RNA Level

Many studies have tested ASOs or RNAi agents to target the CAG repeat.109122 In general, CAG-targeting confers preference towards the expanded allele, as this allows for binding of multiple molecules per mRNA.111 Only a few studies included in vivo efficacy. Yu et al showed the efficacy of their siRNA in HdhQ150 mice.115 Monteys et al used transgenic mice expressing tagged full-length wtHTT and mHTT, showing preferential silencing of mHTT.118 Datson et al showed the efficacy of their CAG-targeting ASO in R6/2 and Q175 mice,120 an ASO that is now further developed by Vico Therapeutics. Kotowska-Zimmer et al have shown that artificial miRNAs targeting the CAG repeat specifically reduced mHTT in YAC128 mice.122

A number of strategies that target other regions of HTT-ex1 have been described as well.123137 This approach would be expected to lower both wtHTT and mHTT. With the exception of Boado et al and Kordasiewicz et al, who used ASOs, all of these studies utilized RNAi agents. Various groups have demonstrated efficacy of siRNA or shRNA in R6/1, R6/2 and AAV100Q mice.127130 uniQures miRNA therapy has shown target engagement in the widest range of HD animal models, including Hu128/21, Q175 and R6/2 mice, lentiviral rat model and transgenic HD minipigs,123,124,132134,136 as well as a favorable safety profile in toxicity studies in rats and non-human primates.137

A handful of studies described other approaches to HTT RNA-targeting. Rindt et al developed a method to induce trans-splicing, by which mHTT exon 1 is replaced with exogenous wtHTT exon 1 in the mRNA. Thus far, there is only in vitro proof of principle for this approach, and the efficiency is rather low, with 1015% of trans-splicing observed even after extensive optimization.138,139 Batra et al have developed an RNA-targeting Cas9 approach which targets the CAG repeat.140 For HD, there is only in vitro evidence for this approach so far, but a similar approach targeting a CUG (cytosine, uracil, and guanine) repeat was shown to be effective in vivo in myotonic dystrophy type 1 mouse models.141 This platform is being developed by Locanabio.

Finally, some small molecules have been described to bind to either HTT-ex1 or the CAG repeat, most notably furamidine, myricetin and a series of pyridocoumarin derivatives, reviewed elsewhere.12 These compounds have been described to inhibit translation of HTT. However, specificity of such compounds is generally low, thereby increasing the chance of unwanted off-target effects.

Finally, several approaches that target the HTT gene have been described (Table 4).

Table 4 Overview of Studies Targeting the HTT Gene

Transcription can be prevented using zinc finger proteins (ZFPs) targeting the expanded CAG repeat.142144 This approach shows allele-selectivity for the expanded repeat and is currently being developed for the clinic by Sangamo and Takeda. Further, CRISPR-Cas9 genome editing approaches have been developed to either knock out HTT by inducing mutations or excise the region containing the CAG repeat. Several groups have shown in vitro and in vivo proof of principle using single guide RNAs directed to HTT-ex1 to induce HTT knockout.145148 Further, using a double guide RNA approach, various groups have shown that it is possible to excise the region containing CAG repeat.149154 The size of this region differs based on the chosen guide RNAs, with the first report by Shin et al deleting a large 44 kb region,149 while the most precise excision was shown by Yang et al and Monteys et al, who deleted only the CAG repeat and small flanking regions.150,151

Several HTT lowering therapies are either already in clinical trials or are close to entering the clinic. These therapies include different therapeutic modalities and mechanisms of action, each with distinct potential efficacy and safety profiles. Only the approaches in clinical trials or performing IND-enabling studies are covered here.

Two of the most advanced programs, the Phase III trial with the non-allele-specific HTT exon 36-targeting ASO tominersen (Roche) and the phase I/II trials with the allele-specific mHTT-associated single nucleotide polymorphism (SNP)-targeting ASOs WVE-120101 and WVE-120102 (Wave Life Sciences) were halted in 2021, as reviewed elsewhere.155 Roche plans to design a new Phase II study with tominersen, for younger adult patients with lower disease burden (https://ir.ionispharma.com/news-releases/news-release-details/ionis-partner-evaluate-tominersen-huntingtons-disease-new-phase). Wave Life Sciences has now initiated a new trial with their novel product WVE-003, which targets another SNP and has improved chemistry (clinicaltrials.gov NCT05032196). These ASOs are administered repeatedly through intrathecal administration, which may explain some of the adverse events observed with tominersen, which was more pronounced in the cohort receiving more frequent administration.155 Neither drug is expected to affect HTT-ex1 formation or RNA-mediated toxicity.

Novartis and PTC Therapeutics both have initiated Phase 2 clinical trials for their splicing modulators Branaplam (NCT05111249) and PTC518 (NCT05358717). These small molecules induce the inclusion of a pseudoexon between HTT exons 49 and 50, which leads to a premature stop codon and subsequent nonsense-mediated decay.156,157 One of the main advantages is that these small molecules can be administered orally. Furthermore, the mechanism of action targets the pre-mRNA and is therefore quite upstream in the molecular pathology. However, this approach is not specific for the mutant allele and, as it targets a downstream exon, is also not expected to affect HTT-ex1 production or toxic RNA gain-of-function.

In a more indirect fashion, metformin has been shown to reduce translation of HTT through interacting with the MID1/PP2A/mTOR protein complex.158 Interestingly, the effect of metformin was found to be specific for mHTT and to also impact HTT-ex1 protein formation. The drug can be administered orally, and as it is already in clinical use for the treatment of diabetes, its safety profile has already been well established. Metformin is currently being tested for the treatment of HD in a phase III clinical trial to establish its potential as a treatment for HD (NCT04826692). Although it has been shown to reduce HTT levels, RNA-mediated toxicity is not expected to be targeted by its mechanism of action.

There are no therapies that target HTT-ex1 exclusively, but some therapies target HTT-ex1 in addition to the full-length HTT. The most advanced is uniQures gene therapy AMT-130, which is currently being tested in phase I/II clinical trials (NCT04120493 and NCT05243017). AMT-130 is an AAV5-delivered miRNA which is administered through a one-time intrastriatal injection. This therapy is not allele-selective, and its effect on RNA-mediated toxicity has not yet been established.

Several other HTT-ex1 targeting candidates are close to entering clinical trials, including Galyan Bios HTT-ex1 binding small molecule GLYN122 and Vybions INT41 intrabody. These therapeutic candidates target the protein and are therefore not expected to impact RNA-mediated toxicity. According to the companies websites, both are performing IND-enabling studies, although their target date to enter the clinic is not clear (https://www.galyan.bio/pipeline, https://www.vybion.com/?page=product_pipeline).

Likewise, Vico Therapeutics received FDA orphan drug designation for their CAG-targeting ASO in July 2021 and is expected to start clinical trials soon (https://vicotx.com/pipeline/). Takeda and Sangamo are further developing their ZFP approach targeting the CAG repeat (https://www.sangamo.com/programs/). Both approaches preferentially target mHTT and as they act on the (pre-)mRNA and on transcription, respectively, these drug candidates may also have a beneficial effect on RNA-mediated toxicity.

Although all the approaches mentioned, as well as others in earlier phases of development, aim to reduce HTT levels, their mechanism of action is different and not all pathways related to HTT toxicity will be engaged. The relative contribution of each pathway is a matter of debate and is likely to depend on many factors, including age, tissue and cell type. Several of the described mechanisms of N-terminal HTT fragment production, including calpain cleavage and premature polyadenylation, have been shown to correlate with repeat length. This is also the case with HTT-ex1 formation through aberrant splicing. Therefore, it may be expected that as the repeat gets longer over time due to somatic instability, the contribution of these mechanisms will increase. Nonetheless, the broad molecular pathology of HD would likely benefit most from an intervention that acts as far upstream as possible, ie, on the DNA or the RNA level.

For an approach to be successful in disease modification, next to efficiency, adequate safety is key. Safety issues can arise from intrinsic characteristics of the therapeutic modality itself (eg, chemistry, properties of the therapeutic vector, and need of chronic administration), which are not covered in this review. The mechanism of action of the approach can also have different safety risks. Very specific approaches, with a well-understood mechanism, and with low to no interactions with other processes and molecules other than those related to HTT toxicity, would be preferred.

Multiple different approaches are running head-to-head. The small molecule splicing modulators are among the most elegant in terms of delivery, as these are capable of crossing the bloodbrain barrier and can therefore be administered orally. However, these small molecules are not specific for mHTT or even solely for HTT, and long-term studies are needed to determine the safety profile. Furthermore, these splicing modulators are expected to affect neither aberrant splicing of HTT-ex1 nor toxic RNA gain-of-function effects. ASOs and siRNAs have a less favorable distribution and need to be administered locally, although novel chemistries, such as peptide nucleic acids and di-siRNAs, have shown more promising biodistribution and may allow for systemic administration. These synthetic oligonucleotides are active for a limited amount of time, and therefore need to be readministered frequently. CAG-targeting ASOs are expected to not only reduce HTT and HTT-ex1 protein gain-of-function but also to alleviate RNA-mediated toxicity; however, non-specific effects on other genes containing CAG repeats may be difficult to overcome. Finally, the gene therapy approaches utilize AAVs to deliver their cargo. The current generation of AAVs is not sufficiently capable of crossing the bloodbrain barrier and therefore still needs to be administered locally, although efforts are ongoing to identify novel capsids that could be administered in a less invasive manner, eg, Goertsen et al.159 Because most cells that are targeted in HD are non-dividing, a more invasive route of administration is, however, less of an issue, as the therapy would only need to be administered once. uniQures miRNA-based strategy would reduce toxic protein gain-of-function, whereas Takeda and Sangamos ZFP approach targets DNA and thereby acts upstream of mHTT transcription, which would improve both toxic protein- and RNA gain-of-function; yet, as the mechanism of action of this approach involves direct targeting of the repeat, off-target effects may be an issue. Pre-clinically, gene editing approaches using CRISPR-Cas are being explored. However, long-term studies will need to show the safety profiles of such approaches.

To maximize therapeutic efficacy, future research will need to point out whether it may be advantageous to combine various therapeutic strategies with different modes of action. Further, it is likely that any therapeutic approach will benefit from as early intervention as possible. To this end, excellent safety profiles and good biomarkers of both safety and efficacy will be key.160

In summary, we have reviewed the production of N-terminal HTT protein fragments, their role in HD pathology, as well as therapeutic approaches to target these toxic species. Extensive research into HD continues to deepen our understanding of the broad molecular mechanisms leading to disease. With the increasing understanding of the pathological mechanisms associated with mHTT, several different therapeutic approaches are being developed, which will hopefully lead, in the near future, to halting or modification of this devastating disease.

We thank our uniQure colleagues who provided a critical review of the manuscript.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

LB, ME and AV are employees of, and may own stock/options in, uniQure biopharma B.V. In addition, Dr Astrid Valls has a patent WO2021053018 issued to UNIQURE IP B.V. The authors report no other conflicts of interest in this work.

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Duchenne muscular dystrophy (DMD) was first described by the French neurologist Guillaume Benjamin Amand Duchenne in the 1860s, though it took until 1986 for researchers to identify a particular gene flaw that leads to the condition. The identification of the dystrophin gene by Louis Kunkel and Jerry Louis opened the door for disease-modifying therapies such as exon-skipping, stop codon readthrough, gene therapy, and CRISPR/cas9 mediated gene editing that focus in on dystrophin restoration.

Currently, there are 4 drugs approved in the United States for mutations amenable to skipping of exons 51, 53, and 45, which are applicable to about 30% of patients total with DMD. Each of these were approved through the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases. At the recently concluded 2022 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) annual meeting, September 21-24, in Nashville, Tennessee, Emma Ciafaloni, MD, gave the Reiner Lecture to a crowd of a few hundred clinicians, highlighting new treatments for DMD.

In her talk, she summarized the expanding pipeline of agents for DMD, how each differs mechanistically, and whether any are more advantageous than another. Ciafaloni, a professor of neurology and pediatrics at the University of Rochester Medical Center, also discussed how to translate new treatments from trials to clinics, the need to improve clinical trial design and process, and how researchers can build on previous successes. Prior to her presentation, as part of a new NeuroVoices, Ciafaloni provided commentary on several topics regarding the DMD pipeline, including the differences and advantages each approach brings, as well as ways to overcome complexities with conducting clinical trials.

Emma Ciafaloni, MD: The exciting research development in the field of Duchenne muscular dystrophy is extraordinary. Many years after understanding the pathophysiology of Duchennewhich the gene wasnt discovered until the late 1980sall that knowledge is finally paying off and opening a window on therapeutic strategies that have to do with disease-modifying gene editing. There are many different approaches now, some like exon skipping, which are already used in the clinics. Some are different stages of development, such as gene therapy in phase three trials. I would be surprised if we didnt have a gene therapy drug in the clinic in the near future. And then CRISPR, which has not been used yet in humans, but has made major milestones and proof of concept in animal models that are highly promising. These are all strategies that are advancing very rapidly, I think that the field is moving much faster than in the past because of the collaboration between pharma and academia, and the patients and the families. There are many clinical trials in Duchenne, and it's a very exciting time.

Also, there has never been a time before in muscular dystrophies in general, not just Duchenne, where there were so many different, new ideas, as well as old ideas that finally started working in humans. The second part of my talk briefly covered other treatments, ideas and strategies that are not directed to restoration of dystrophin. They're not genetic treatments, but they work more on the downstream pathology of muscle degeneration into Duchenne, like the fibrosis, inflammation, and regeneration. There are some interesting drugs out there, probably a few that are going to be approved soon. We're looking at probably a multifactorial type of treatment, it may be a combination treatment. It's never been a richer time in terms of treatments for Duchenne. Also, it's exciting because some of the lessons learn, for example, with the genetic treatments, are extremely helpful for the larger field of neuromuscular diseases and even neurology. The learning has been fantastic.

With spinal muscular atrophy leading the way, we're moving into more muscle-based diseases [with gene therapy], but the lessons learned are still very valuable. Additionally, we have seen this collaboration between different sponsors, pharmaceuticals, and academias to share the learning, because that's just going to help move things faster and better and in a safer way. That is a positive phenomenon that is unprecedented, and it's helping to accelerate the science in a safe and effective way.

There are still many questions that remain. All these genetic modification approaches have been exon skipping, or gene therapy replacement. They don't replace the full-length dystrophin because it's a very large gene. It's a biologically modified type of dystrophin, so there is no doubt that it will have a profound benefit, but I think that there is plenty of room for improvement. Obviously, gene therapy is not approved yet, so remains to be seen in terms of clinical improvement. But even in the exon skipping, I think that we're going to see much more exciting next generation, exon-skipping that people are currently working on very hard on. The field of science and medicine always evolves. What we have now is only going to be much better down the road in a few years. I have no doubt, and the community of Duchenne is working very hard to make even the drugs that we have now, better.

Sometimes, for the more general neurologist or certainly for the general public, it's important to remember that when we talk about Duchenne muscular dystrophy, or many of our neuromuscular diseases that we discuss here at AANEM, these are also rare diseases. The definition from the FDA for a rare disease is less than 200,000 total patients in the United States. For Duchenne, for example, we're talking about maybe around 12,000 patients. This is not [multiple sclerosis], or Parkinson disease or Alzheimer disease. There are challenges in clinical trial designs that are unique, and they need to be understood. Some of the accelerated approval for some of these drugs is part of that challenge and difference. For example, especially with the genetic approach, some of these genetic approaches like exon skipping, only target a specific mutation in maybe 10% to 13% of patients. Now you're taking a subgroup of an ultra-rare disease that is only 10% of that population. Then you need to run clinical trials that are going to have a chance to prove a difference, and so, you restrict the inclusion criteria to a specific age. Then you're really challenged to find enough patients to do well in a placebo-controlled trial. It's important to keep that in mind that there is plenty of room for improvement in making our rare disease clinical trial design more effective, less time consuming for patients, and improving the approval path.

I also want to say that in Duchenne, the amount of data that has been produced in the past several years in terms of motor endpoints, natural history, the six-minute walk test, the North Star [Ambulatory Assessment], etc. These outcome measure prospective cohorts have been incredibly invaluable. This is just to recognize the incredible amount of work that researchers and families and patients have done in the past several years that is helping the field immensely. We are at a different time, its an exhilarating, exciting time. I think that the community of rare diseases like Duchenne have been incredibly, hard-working in a good, cohesive way to advance the field forward, which is very refreshing.

Transcript edited for clarity. Click here for more NeuroVoices.

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NeuroVoices: Emma Ciafaloni, MD, on the Vast Expansion of Innovative Approaches to Duchenne Muscular Dystrophy - Neurology Live