Category Archives: Gene therapy

CAMBRIDGE, Mass., Oct. 03, 2022 (GLOBE NEWSWIRE) -- Voyager Therapeutics, Inc.(Nasdaq: VYGR), a gene therapy and neuroscience company developing life-changing treatments and next-generation adeno-associated virus (AAV) capsids, today announced that it will present three posters at the upcoming 29th Annual Congress of the European Society of Gene & Cell Therapy (ESGCT), taking place October 11-14, 2022, in Edinburgh, Scotland.

Poster Presentation Details:

Presentation Title: Identification of a Cell Surface Receptor Utilized by an Engineered BBB-Penetrant Capsid Family withEnhanced Brain Tropism in Non-Human Primates and MicePoster Number: P024Presenting Author: Brett Hoffman, Ph.D., Senior Scientist, Capsid Discovery

Presentation Title: Dose-Response Evaluation of 9P801, an Engineered AAV Capsid with High BBB Penetration and CNS Transduction in Non-Human PrimatesPoster Number: P015Presenting Author: Mathieu Nonnenmacher, Ph.D., Vice President, Capsid Discovery

Presentation Title: Evaluation of an Early, Late, Very Late Expressed Rep in a Recombinant Baculovirus to Produce a More Potent AAV-based Gene Therapeutic in Insect CellsPoster Number: P065Presenting Author: Jeffrey Slack, Ph.D., Principal Scientist, Cell Culture Development

AboutVoyager TherapeuticsVoyager Therapeutics(Nasdaq: VYGR) is leading the next generation of AAV gene therapy to unlock the potential of the modality to treat devastating diseases. Proprietary capsids born from the Companys TRACER discovery platform are powering a rich early-stage pipeline of programs and may elevate the field to overcome the narrow therapeutic window associated with conventional gene therapy vectors across neurologic disorders and other therapeutic areas. voyagertherapeutics.com LinkedIn Twitter

Voyager Therapeutics is a registered trademark, and TRACER is a trademark, ofVoyager Therapeutics, Inc.

ContactsInvestorsInvestors@vygr.com

MediaPeg Rusconiprusconi@vergescientific.com

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Voyager Therapeutics Announces Data Presentations at the 29th Annual Congress of the European Society of Gene & Cell Therapy - GlobeNewswire

Researchers at the National Eye Institute have designed a gene therapy approach that could help prevent blindness in children with Leber congenital amaurosis, a rare form of blindness.

A discovery by the National Eye Institute (NEI), part of the National Institutes of Health, could lead to a second gene therapy for a rare form of blindness. The researchers discovered that a type of Leber congenital amaurosis (LCA) is caused by mutations in the NPHP5 (also called IQCB1) gene and leads to severe defects in the primary cilium, a structure found in nearly all cells of the body. Primary cilia play a role in cell cycle regulation. In the eye, cilia play important roles in maintaining normal eye function.

Leber congenital amaurosis is an eye disorder that affects the tissue at the back of the eye that detects light and color. It is also associated with sensitivity to light, involuntary movements of the eye, and extreme farsightedness. Leber congenital amaurosis affects 2 to 3 per 100,000 newborns and is one of the most common causes of blindness in children.

There are at least 13 types of Leber congenital amaurosis, according to the National Library of Medicine. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities. One gene therapy has already been approved to treat a degenerative eye disease. It is available for blindness associated with a mutation of RPE65, which provides the instructions for making a protein important for normal vision. In 2017, the FDA approved Spark Therapeutics Luxturna (voretigene neparvovec-rzyl), the first one-time gene therapy for patients with RPE65 mutation-associated retinal dystrophy and viable retinal cells.

The type of Leber congenital amaurosis caused by mutations in NPHP5 is relatively rare. In a healthy eye, NPHP5 protein is believed to help filter proteins that enter the cilium. Previous studies in mice have shown that NPHP5 is involved in the cilium, but researchers didnt know the exact role of NPHP5.

NPHP5 deficiency causes early blindness in its milder form, and in more severe forms, many patients also exhibit kidney disease along with retinal degeneration, the studys lead investigator, Anand Swaroop, Ph.D., senior investigator at the NEI Neurobiology Neurodegeneration and Repair Laboratory, said in a press release. Weve designed a gene therapy approach that could help prevent blindness in children with this disease and one that, with additional research, could perhaps even help treat other effects of the disease.

Three post-doctoral fellows, Kamil Kruczek, Ph.D., Zepeng Qu, Ph.D., and Emily Welby, Ph.D., at the National Eye Institute collected stem cell samples from two patients with NPHP5 deficiency at the NIH Clinical Center. These stem cell samples were used to generate retinal organoids, cultured tissue clusters that possess many of the structural and functional features of actual, native retina.

The found reduced levels of NPHP5 protein within the patient-derived retinal organoid cells, as well as reduced levels of another protein called CEP-290, which interacts with NPHP5 and forms the primary cilium gate. They also found that photoreceptor outer segments in the retinal organoids were missing and the opsin protein a light sensitive protein that should have been localized to the outer segments was instead found elsewhere in the photoreceptor cell body.

Researchers introduced an adeno-associated viral (AAV) vector a virus that is used mechanism to deliver the gene containing a functional version of NPHP5. The retinal organoids showed a restoration of opsin protein concentrated in the proper location in outer segments. The findings also suggest that functional NPHP5 may have stabilized the primary cilium gate.

The study was funded by the NEI Intramural program.

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Researchers Develop Potential Gene Therapy to Treat Blindness - Managed Healthcare Executive

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...

Sanofi will partner with the Californian biotechnology company Scribe Therapeutics in a deal that extends its exploration of new ways to build cancer cell therapies.

Under a partnership announced Tuesday, Sanofi will pay Scribe $25 million upfront to gain access to the five-year-old startups gene editing technology. The pharmaceutical company is also promising more than $1 billion in additional payments based on unspecified development and commercial milestones, although that money may never be paid out.

In return, Sanofi gets non-exclusive rights to use Scribes CRISPR-based gene editing technology to develop cancer treatments constructed from modified natural killer, or NK, cells. A type of immune defender, NK cells have drawn increasing interest from cancer drugmakers looking for alternatives to the T cells used in CAR-T treatments for leukemia, lymphoma and multiple myeloma.

This collaboration with Scribe complements our robust research efforts across the NK cell therapy spectrum and offers our scientists unique access to engineered CRISPR-based technologies as they strive to deliver off-the-shelf NK cell therapies and novel combination approaches that improve upon the first generation of cell therapies, said Frank Nestle, Sanofis head of research and chief scientific officer, in a statement.

Sanofi missed the first wave of cancer cell therapy development, which companies like Novartis, Gilead and, more recently, Bristol Myers Squibb have led. But it appears interested in making up ground with bets on newer technologies.

In November 2020, Sanofi bought Kiadis Pharma and its pipeline of donor-derived NK cell therapies. Five months later, the company acquired Tidal Therapeutics, which was attempting to use messenger RNA to reprogram immune cells in the body to attack cancers.

While a much smaller financial commitment, the partnership with Scribe could help Sanofi better develop NK cells therapies. Scribes gene editing technology relies on the CRISPR framework pioneered by its cofounder Jennifer Doudna, but the company has developed its own DNA-cutting enzymes, too.

Scribe raised $100 million in a Series B round last spring and in March hired ex-Barclays banker David Parrot as its chief financial officer. In an interview with CFO Dive, Parrot said he had been brought on to help eventually launch an initial public offering, but noted the company would focus first on inking partnerships as public markets remain cool to IPOs.

The deal with Sanofi is the second Scribe has disclosed publicly. Its also working with Biogen on a research collaboration focused on ALS and another undisclosed disease.

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Sanofi partners with Scribe to gain gene editing tools for cell therapy work - BioPharma Dive

FLORHAM PARK, N.J., Oct. 04, 2022 (GLOBE NEWSWIRE) -- Real Endpoints, the leading market-access platform and advisory firm, announced a collaboration with bluebird bio, inc. (Nasdaq: BLUE), to provide multiple health plans with access to an innovative, outcomes-based agreement for ZYNTEGLO (betibeglogene autotemcel) through the Real Endpoints (RE) Marketplace.

These plans cover nearly 16 million individuals across the U.S.; while treatment-dependent beta-thalassemia is a rare disease, together these plans comprise a significant portion of the patient population in the U.S. ZYNTEGLO is currently the only FDA-approved gene therapy for people with beta-thalassemia who require regular red blood cell transfusions.

Through a single contract, the plans in RE Marketplace can take immediate advantage of bluebirds innovative agreement, which offers rebates of up to 80% if treatment with ZYNTEGLO does not enable a patient to achieve and maintain transfusion independence in the two years following therapy.

RE Marketplace performs all the required analytics and financial reconciliation as an expert, independent third-party. RE Marketplace provides participating plans and manufacturers with end-to-end capabilities for efficient, scalable value-based contracting and does so with complete financial and data transparency.

bluebirds ZYNTEGLO is a giant step forward for medicine, commented Jane Barlow, MD, Chief Clinical Officer at Real Endpoints. The plans in RE Marketplace are thrilled to be able to easily access bluebirds innovative risk-sharing agreement, which speeds the delivery of both clinical and economic innovations. That is a win for both patients and the broader health system, she said.

About RE Marketplace

The RE Marketplace platform provides members of mid-sized and smaller health plans speedier access to innovative treatments such as rare disease drugs, cell and gene therapies, and digital medicines. From four founding member plans, RE Marketplace now represents several mid-sized and regional plans approaching nearly 16 million beneficiaries across all lines of business. Both industry and payer participants benefit from the efficiency and flexibility of RE Marketplace, which can support a range of innovative contracts through a standard contracting process. There is also the potential for more generous rebate opportunities without additional Medicaid Best Price risk. RE Marketplace performs all the critical analytics and financial reconciliation transparently and with full audit rights, using a highly robust, secure, HIPAA-compliant system already tested and used in multiple value-based agreements. For more about RE Marketplace, please visit this link: https://realendpoints.com/products/re-marketplace/

About Real Endpoints

Real Endpoints solutions create patient access to meaningful medical innovations and prepare companies for competition in the value-based economy. Working collaboratively with biopharma, diagnostic and medical device companies, RE provides unique answers across a wide range of coverage and reimbursement issues from pricing and distribution to patient support services. RE is also the leading advisor to the industry on innovative contracting, including the evaluation, structuring, negotiating, and third-party management of the analytics and financial reconciliation of value-based contracts. For more information about Real Endpoints, visit http://www.realendpoints.com.

Website: http://www.realendpoints.comLinkedIn: https://www.linkedin.com/company/real-endpoints/

Contact: Aurore Duboille Email: aduboille@realendpoints.comPhone: 973-805-2300

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Real Endpoints Marketplace announces collaboration with bluebird bio to help scale delivery of a first-of-its-kind value-based contract for one-time...

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.

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

MIAMI--(BUSINESS WIRE)--The 2022 Cell & Gene Meeting on the Mesa annual conference will be held in Carlsbad, California, on October 11-13, 2022, bringing together senior executives and top decision-makers in the industry to advance cutting-edge research into cures. Tackling the commercialization hurdles facing the cell and gene therapy sector today, this meeting covers a wide range of topics from clinical trial design to alternative payment models to scale-up and supply chain platforms for advanced therapies. Meet with the OrganaBio team to learn about our reliable supply of high-quality, ethically sourced tissue and cellular raw materials with clear paths to clinical translation, and the advanced processing and characterization capabilities we offer to speed up novel therapeutic development.

OrganaBios CEO, Justin Irizarry, and VP of Corporate Development, Dr. Priya Baraniak, will join the over 1,700 attendees, and will be available for one-on-one meetings to discuss available solutions to cell therapy developers.

http://www.organabio.com

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Meet with the OrganaBio executives in-person at The Cell & Gene Meeting on the Mesa - Business Wire

Atsena Therapeutics

ATSN-101 demonstrated clinically meaningful improvements in vision with no drug-related serious adverse events

Data presented at the American Academy of Ophthalmology 2022 Annual Meeting

DURHAM, N.C., Oct. 03, 2022 (GLOBE NEWSWIRE) -- Atsena Therapeutics, a clinical-stage gene therapy company focused on bringing the life-changing power of genetic medicine to reverse or prevent blindness, announced positive results from the Phase I/II clinical trial of ATSN-101, its lead investigational gene therapy product formerly known as SAR439483, for the treatment ofGUCY2D-associated Leber congenital amaurosis (LCA1).

The data demonstrated that subretinal delivery of ATSN-101 was well tolerated and patients treated with the highest dose (1.0E11 vg/eye) saw clinically meaningful improvements in vision, as measured by full-field stimulus testing (FST) and multi-luminance mobility testing (MLMT), at more than one-month post treatment.

As of the July 25, 2022, data cut-off date, 15 patients, including three pediatric patients, were treated with ascending doses of ATSN-101. Patients treated with the highest dose (N=9) demonstrated a significantly larger mean change from baseline in retinal sensitivity and a trend toward a larger mean change in best-corrected visual acuity (BCVA) in treated eyes as compared with untreated eyes. In addition, three of four patients tested on MLMT demonstrated at least two-level improvement from baseline light levels. No drug-related serious adverse events were reported, and most treatment-emergent adverse events were mild and transient.

Patients with LCA1 have profound visual impairment or blindness at birth, but their retinal structure remains intact, which indicates an opportunity to confer meaningful improvements following delivery of a subretinal gene therapy such as ATSN-101, said Kenji Fujita, MD, Chief Medical Officer of Atsena Therapeutics. Were encouraged by these data that demonstrate ATSN-101 improved visual function while maintaining a favorable safety profile. We look forward to launching a pivotal trial for the evaluation of ATSN-101, which will lay the groundwork for successful registration and commercialization. We also look forward to advancing other promising programs in our gene therapy pipeline to reverse or prevent blindness for people with inherited retinal diseases.

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The data were presented on Saturday, Oct. 1, in a Late Breaking Developments session during the Retina Subspecialty Day at the American Academy of Ophthalmology Annual Meeting (AAO 2022) in Chicago, by Christine Nichols Kay, MD, Clinical Ophthalmology Advisor for Atsena.

About GUCY2D-associated Leber congenital amaurosis (LCA1)LCA1 is a monogenic eye disease that disrupts the function of the retina. It is caused by mutations in the GUCY2D gene and results in early and severe vision impairment or blindness. GUCY2D-LCA1 is one of the most common forms of LCA, affecting roughly 20 percent of patients who live with this group of inherited retinal diseases. There are currently no approved treatments for LCA1.

About Atsena TherapeuticsAtsena Therapeutics is a clinical-stage gene therapy company developing novel treatments for inherited forms of blindness. The companys ongoing Phase I/II clinical trial is evaluating a potential therapy for a form of LCA, one of the most common causes of blindness in children. Its additional pipeline of leading preclinical assets is powered by an adeno-associated virus (AAV) technology platform tailored to overcome significant hurdles presented by inherited retinal disease, and its unique approach is guided by the specific needs of each patient condition to optimize treatment. Founded by ocular gene therapy pioneers Dr. Shannon Boye and Sanford Boye of the University of Florida, Atsena is based in North Carolinas Research Triangle, an environment rich in gene therapy expertise. For more information, please visitatsenatx.com.

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

Business Contact:info@atsenatx.com

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Atsena Therapeutics Announces Positive Results from Phase I/II Clinical Trial of ATSN-101 for the Treatment of GUCY2D-associated Leber Congenital...

Gene therapy is a novel therapeutic approach to managing various inherited and acquired diseases. Gene therapy has already successfully managed (i) inherited diseases such as Leber's congenital amaurosis (LCA), X-linked severe immunodeficiency disease, beta thalassemia, hemophilia, and chronic granulomatous disease; and (ii) acquired diseases such as multiple myeloma, B-cell lymphoma, advanced melanoma, prostate cancer, and many others [1]. The eye is an ideal organ for gene therapy. This is attributed to the fact that it is small, easily accessible, and isolated; it has a blood-retinal barrier; and the other eye can act as a control. It requires a lower dose of vectors. There is little to no chance of systemic infection using viral vectors [2]. Gene therapy can be either ex vivo or in vivo. Ex-vivo gene therapy is when the host cells are collected, cultured, genetically modified, and transplanted back into the host. In vivo means when the genetically modified information is transferred to targeted host cells via viral or non-viral vectors [3]. The viral vectors use the inherent property of viruses to infect the host cell's genomes. The pathological genetic sequence is replaced by the therapeutic genes, which can produce the desired therapeutic effect.

The non-viral vectors transfer either DNA plasmids or small DNA and RNA molecules by physical or chemical methods. Physical methods include electroporation, sonoporation, hydroboration, needles, and DNA ballistics. The chemical methods include using vectors like inorganic particles, lipids, polymers or peptide particles [4]. Ocular gene therapies can be used for various inherited retinal diseases like Lebers congenital amaurosis, X-linked retinitis pigmentosa (RP), choroideremia, X-linked retinoschisis, Stargardt disease, and Usher syndrome, which are discussed in this review [3]. Various clinical trials for corneal gene therapy are also being done for corneal dystrophies, herpes simplex virus keratitis, Sjogren syndrome, and others [5]. Ocular gene therapy is not only used for inherited diseases but also acquired diseases like glaucoma. Few clinical trials have been conducted for glaucoma where the therapeutic gene, i.e., siRNA, antagonizes adrenergic receptor synthesis to lower the intraocular pressure [6]. Even if much progress has been made in ocular gene therapy, there are several challenges that we have yet to overcome. This includes uncertainty about the longevity and irreversibility of the therapy. Other challenges include gene therapy complications like ocular inflammation, insertional oncogenesis, or therapeutic failure.

Gene Replacement/Gene Augmentation

Gene augmentation is most commonly used for autosomal recessive disorders. In these disorders, a defect or absence of a single copy of the gene leads to loss-of-function mutation and thus to an inadequate amount of protein synthesis. In gene augmentation, the abnormal copy of the gene is replaced by the normal copy of the gene via therapeutic vectors. This therapeutic gene can be transferred either as mRNA or as a DNA copy [7]. DNA needs to be injected directly into the nucleus of the cells. It also increases sustained production of the protein, hence it is preferred. The complications of using mRNA include instability of the mRNA molecule due to changes in sequence within it and the induction of immune responses. The disadvantage of gene augmentation is that it cannot be used in an already degenerated retina. This technique has been successfully used for Food and Drug Administration (FDA) approved Phase 3 trial of Luxturna, a gene product used to treat Leber's congenital amaurosis targeting gene RPE65. The RPE65 gene encodes for retinoid isomerohydrolase, an enzyme of the visual cycle synthesized by the retinal pigment epithelium (RPE) [7,8].

Gene Silencing/Gene Editing

This mechanism is used for autosomal dominant inherited diseases. Here, the mutation is a gain-of-function mutation. The disease occurs due to the expression of undesired proteins or gene products of the mutated gene. The aim is to prevent the mutated gene from expressing and encoding the undesired protein. This can either be allele-specific or non-specific. In allele-specific, only the mutated allele is targeted. In allele non-specific, both the mutated and the functional allele are silenced and, by gene augmentation, replaced with the normal gene. It can be done at three levels of the genetic machinery: (1) DNA, (2) RNA, and (3) transcription [3].

CRISPR/Cas9

CRISPR are clustered regularly interspaced short palindromic repeats of prokaryotic DNA. The virus genome follows each repetitive sequence from a previous infection, known as spacer DNA. Cas9 is a CRISPR-associated protein 9 that specifically cuts DNA at these recognizing sites, leading to gene silencing [9]. When used for genome editing, Cas9 endonuclease, along with guide RNA, is injected into the nucleus of target cells. The RNA-guided endonuclease cuts the double-stranded DNA at targeted sites, activating the DNA repair system [3]. This technique has been used therapeutically for autosomal dominant RP [10].

Other DNA-based genome editing techniques are transcription activator-like effector nucleases (TALENs) and zinc finger nucleases (ZFN) [11]. There are ongoing clinical trials to treat acquired immune deficiency syndrome using the ZFNgenome editing technique targeting the C-C chemokine receptor type 5 gene (CCR5 gene) of CD4+T cells (T helper cells). CCR5 is present on the surface of these cells and acts as a coreceptor for the human immunodeficiency virus. In this trial, the CCR5 gene was silenced by genome editing using the ZFN technique[12].

These techniques work either by eliminating mRNA molecules or preventing their translation.

Small Interfering RNA

RNA interference (RNAi) is a post-transcriptional gene silencing technique that uses sequence-specific siRNA to cleave targeted RNA. The RNAi pathway starts with long pieces of dsRNA being cleaved into small interfering RNA by the endoribonuclease dicer enzyme. This step can be skipped by directly administering siRNA into the targeted cell cytoplasm. Once in the cytoplasm, the siRNA gets incorporated into a protein complex called the RNA-induced silencing complex (RISC). The double-stranded siRNA gets cleaved into sense and antisense strands. The antisense strand guides the RISC to the targeted mRNA and cleaves it, preventing gene expression. RNA interference is currently under trial for managing age-related macular degeneration, glaucoma, RP, and diabetic retinopathy [3,13].

Antisense Oligonucleotide

These are complementary strands of the targeted mRNA molecule. It causes the downregulation of gene expression by two mechanisms. An antisense oligonucleotide binds to the targeted mRNA and forms a complex. The mRNA and antisense oligonucleotide complex are cleaved by RNaseH1 activity. The other mechanism acts by translation inhibition, preventing exon splicing, 5'mRNA capping, or destabilizing the RNA. Currently, the antisense oligonucleotide is under trial for ocular gene therapy for Lebers Congenital Amaurosis acting on the gene CEP290. This gene encodes for centrosomal protein 290 [14,15].

Characteristics of the vectors are summarized in Table 1.

Several ongoing clinical trials are conducted by ocular gene therapy ranging from retinal to corneal diseases [20]. Table 2 summarizes a few clinical trials, including completed and ongoing trials, which are discussed further.

LCA is a childhood-onset autosomal recessive disease that leads to vision loss. It occurs due to the mutation of several genes, especially RPE65, encoding for retinoid isomerohydrolase, which is predominantly expressed in the retinal pigmented epithelium. This mutation leads to a deficiency of the enzyme retinoid isomerase, which is responsible for chromophore formation. Chromophore forms visual pigments in photoreceptors of the retina. This leads to visual impairment [18].

The first approved ocular gene therapy by the FDA is the phase 3 trial of Luxturna sub-retinal injection for LCA in both eyes. The gene product was AAV2-hRPE65v2 (voretigene neparvovec-rzyl), and the vector was adeno-associated virus 2 (NCT00999609) [21]. The inclusion criteria consisted of participants being three years or older, being a diagnosed case of LCA with RPE65 mutation, visual acuity of less than 20/60 in both eyes with the best possible correction. The subjects should be evaluated by multi-luminance mobility testing (MLMT). The most important inclusion criteria were the presence of viable retinal cells as determined by optical coherence tomography (OCT). The outcome was measured by MLMT, which is used to measure functional vision changes. The MLMT score ranged from 0 to 6, with six being where the subject was able to pass MLMT with low light intensity. The MLMT score change was a difference between the baseline score and the score measured after a year. The other measures for the trial's outcome were full-field light sensitivity threshold testing and visual acuity. The trial results indicated that the MLMT change score in the interventional group was 1.8 as opposed to the control group, with an MLMT change score of 0.2. This indicated an improvement in functional vision by Voretiegene Neparvovec gene replacement therapy [8].The adverse effect has been described in Table 3.

The only serious complications were convulsions in one participant out of 20 participants with a history of pre-existing seizure disorder and adverse drug reactions in a participant with a history of complicated oral surgery and pre-existing seizure disorder. The gain in visual function has been present for over three years. However, the durability of the intervention is still not determined [8]. Other clinical trials for LCA are mentioned in Table 4.

RP is a group of disorders that cause progressive retinal dystrophy and vision loss. It is one of the most common causes of vision loss. One in every 4000 individuals worldwide is affected by RP. RP can be either autosomal dominant, autosomal recessive, or X-linked. Autosomal recessive is the most common. More than 70 genes are found to be concerned with the development of retinitis pigmentosa [18].

Optogenetic Therapy for Advanced Retinitis Pigmentosa

The clinical trial (NCT03326336) is the most advanced novel ongoing clinical trial for the management of advanced stages of retinitis pigmentosa, combining gene therapy, engineering, and mechanics. It does not target mutated photoreceptors; thus, the mutation is independent. It targets retinal ganglion cells, bypassing the rest of the pathway. The ganglion cells are injected with an optogenetic vector, AAV2.7m8, which encodes for light-sensing proteins CrimsonR and tdTomato. This transgene vector is injected via a single intravitreal injection followed by the use of engineered goggles, GS030MD, that sense light changes in their vicinity and project them into the genetically modified ganglion cells. The objective of this clinical trial was to check the safety of the gene product and the recovery of vision. The clinical trial till now has reported partial vision recovery in one out of 15 participants. The participant, using light-stimulating goggles following gene therapy, could perceive and locate the objects. The therapy was well tolerated, and no intraocular inflammation or other changes were noted. This indicates that optogenetic gene therapy, along with light-stimulating goggles, can be used to partially restore vision in advanced RP [22,23].

Autosomal Dominant Retinitis Pigmentosa

RHO (Rhodopsin) gene was responsible for about 25% of all cases of autosomal dominant retinitis pigmentosa (ADRP). The RHO gene transcribes the RHO protein. RHO protein is the visual pigment present in the rods' outer segments. There are two possible clinical scenarios in ADRP. In class A, there is an early presentation with severe progressive loss of rods. The main aim of the therapy here is to preserve the functions of the cones. In class B, there is a slow progression, and the functions of the rods are well preserved. Here, the main aim of the therapy will be the preservation of the rods. The most common mutation in the RHO gene is the substitution from proline to histidine at the 23rd position (P23H) [10]. The ongoing clinical trial, NCT04123626, targets the P23H mutation of the RHO gene. The gene product used here is QR-1123. It is an antisense oligonucleotide, which is an ssDNA molecule complementary to the targeted P23H mRNA, which increases expression of the wild type of the RHO protein in photoreceptors [24].

MERTK-Associated Retinitis Pigmentosa

One of the other genes involved in the pathogenesis of RP is the MER tyrosine kinase gene (MERTK). The photoreceptors in the retinal epithelium recycle their outer segments. The shed outer segments of the photoreceptors are phagocytized by MERTK [25]. The current clinical trial for MERTK-associated RP (NCT01482195) delivers unilateral subretinal rAAV encoding MERTK protein. This trial aimed to assess the safety of the gene product rAaV2-VMD2-hMERTK. The collected data indicated that three out of six participants showed visual improvement, which lasted for two years in two of these participants. The adverse effects of this clinical trial are summarized in Table 5. Other than these adverse effects, the clinical trial was found to be safe.

Age-related macular degeneration is one of the most common causes of irreversible blindness. It consists of two phases: (1) dry or non-neovascular and (2) wet or neovascular. During the non-neovascular phase, there is atrophy of the retinal cells in patches, called geographic atrophy, leading to loss of central vision. During the neovascular phase, there is the formation of new blood vessels originating from the choroid into the sub-retinal space. These vessels cause leakage of fluid into the subretinal space as they lack tight junctions. The subretinal space is filled with fluid, leading to oedema and reversible vision loss. However, if this fluid build-up continues for several months, it may cause irreversible vision loss [27]. The vascular endothelial growth factor is responsible for the proliferation of new vessels. Hence, the current standard therapy for neovascular macular degeneration is intravitreal drug administration of anti-VEGF agents. However, considering the economic and social burden this therapy puts on because of the repeated intravitreal injections, complications, high drug cost, and repeated imaging, ocular gene therapy for sustained drug delivery have become necessary [28].

The current clinical trials can have two mechanisms: either by the sustained release of anti-angiogenic factors or by gene silencing for factors that cause overexpression of VEGF [29]. The current trials are summarized in Table 6.

Pigment Epithelium-Derived Factor

The first clinical trial for neovascular age-related macular degeneration was conducted by targeting the gene for pigment epithelium-derived factor (PEDF) protein. The NCT number for the clinical trial is NCT00109499 [30]. PEDF is usually present in the eye, acting as an anti-angiogenesis factor. Its levels are altered in neovascular macular degeneration. The transgene was delivered via the intravitreal route as AAV2 expressing PEGF. The adverse effects occurred in 25% of the cohort population and were limited to mild ocular inflammation and a slight increase in intraocular pressure, which were easily manageable. The results of this trial had a dose-related effect. The cohorts receiving the dose of 108 particle units showed no increase in the lesion and a significant decrease in neovascularization. Whereas the cohorts receiving doses less than 108 showed an increase in the size of lesions by one disk area at 12 months. This suggests that this ocular gene transfer is a feasible approach and further studies should be carried out [31].

Aflibercept

Aflibercept is an anti-VEGF factor that acts as a receptor for VEGF-A, VEGF-B, and placental growth factors, preventing neovascularization. Aflibercept is a fusion protein encoded by different genes [29]. The clinical trial (NCT03748784) studied the safety and efficacy of the gene product ADVM-022, responsible for the sustained release of aflibercept. The vector used here is AAV-2, administered by the intravitreous route. After 34 weeks, ADVM-022 was well tolerated. Only mild ocular inflammation was observed and resolved by steroid eye drops. Consistent improvements were seen on OCT, and patients maintained vision throughout [32].

Endostatinand Angiostatin

Endostatin and angiostatin inhibit angiogenesis endogenously. The clinical trial (NCT01301443) is a dose escalation study to determine the safety and efficacy of a lentiviral vector administered subretinally for sustained expression of endostatin and angiostatin [33]. The procedure caused a macular hole in one of the participants. However, it was very well tolerated by others. Eight participants showed sustained expression of angiostatin and endostatin for a period of 2.5 years, whereas two participants showed sustained release for four years [29,34].

sFLT-1

FLT-1 is a receptor gene that endogenously inhibits VEGF-A, preventing angiogenesis. Currently, there are two clinical trials that focus on viral vector-delivered sFLT-1.

The clinical trial (NCT01494805) delivers rAAV.sFlt-1 via the AAV2 vector subretinally, which encodes naturally occurring FLT-1. No particular adverse effects were seen. It was found to be safe and tolerable, especially among the geriatric population, and could help decrease the frequency of anti-VEGF injections. However, no significant improvement in visual acuity or other exploratory points was observed [28,35].

The other clinical trial (NCT01024998) delivered AAV2-sFLT01 via the vector AAV-2 by the intravitreous route. The viral vector encoded a fusion protein of sFLT-1 domain two and the Fc domain of Immunoglobulin G1. It was a dose escalation study, which showed that the gene product was well tolerated at all doses. It was observed that 5 out of 10 participants who were administered higher doses showed a detectable amount of sFLT-1 levels. The participants, who did not express sFLT-1, had an antibody titre of 1:400 against the AAV-2 vector. The clinical trial did not particularly show any improvement in visual acuity or retinal thickness [28,29,36].

One of the major setbacks of ocular gene therapy is inflammation. The eye is considered a site of immune privilege due to varying factors like the retinal-blood barrier. However, the immunogenicity of viral vectors, their capsids, the transgene, and the transgene product as a foreign body can activate immune responses. Various factors affect the severity of the immune response, such as viral vectors used, administration route, and viral dose, including several others [37].

Type of Vector

AV is currently only used for the gene therapy of retinoblastoma as it is highly immunogenic. It causes severe inflammation and destruction of the transduced cell. Being a double-stranded virus, it binds strongly to TLR9 and activates a stronger immune response.

AAV has several serotypes which have different levels of immunogenicity. Most of the population normally has pre-existing antibodies against AAV2, and a small part of the population has antibodies against AAV8. However, cross-reactivity between serotypes is possible. AAVs only generate favourable immune responses, hence they are the preferred vector for ocular gene therapy [37].

LV generates a stronger immune response than an adeno-associated virus but is preferred when more genetic material needs to be transduced [18,38].

Route of Administration

Different routes of delivery expose the vector to different systemic and local biodistribution. The intravitreal route is the most commonly used but shows a higher immune response. This is because the viral particles from the vitreous, through Schlemms canal and reach the systemic circulation and lymphatic flow and can activate an immune response. The subretinal space is relatively immune-privileged and shows a very mild immune response [37].

Viral Dose

According to Timmers et al., the relationship between the viral dose and ocular inflammation depends upon the site of inflammation. In the anterior chamber, the dose escalation did not show any effect. However, in the vitreal chamber, dose escalation showed a greater degree of immune response [39].

The basis of gene therapy is to replace or inactivate a faulty gene or administer a gene product that can prevent the disease process. Ocular gene therapy, in particular, has proven to be a promising tool to treat many inherited retinal diseases like RP, LCA, choroideremia, Stargardt disease, and acquired diseases like nAMD, glaucoma, and diabetic retinopathy. Several clinical trials are being conducted, though in their early stages, have shown promising results. The aim of any clinical trial is to assess the safety and efficacy of the gene product. Something to be concerned about when it comes to the safety of ocular gene therapy is inflammation. There are several factors that affect it such as the vectors used, the route involved, and the dose of the gene product. The subretinal route generates a milder immune response compared to the intravitreal route. AAVs are currently preferred, though newer viral vectors should be considered. As we already know what factors affect it, vectors and delivery methods need to be developed to prevent ocular inflammation. Factors that influence the selection of a vector are immunogenicity, size, the amount of genetic material it can carry and the adverse effects it generates, if any. There are several unanswered questions when it comes to the sustainability of ocular gene therapy. We still do not know how long the effect of gene therapy will last, what factors will affect it and how they can be influenced. Another issue that needs addressing is the long-term adverse effects of gene therapy.

As we have seen in the review, there are several gene targets when it comes to nAMD. A combined approach with several gene targets for such diseases can be developed. A thorough study of the molecular genetics of the disease needs to be done to have a positive outcome in such a case. Though ocular gene therapy has made massive progress in retinal diseases, gene therapy for other ocular diseases like uveitis, corneal graft rejection, and corneal genetic dystrophies needs to be addressed. Ocular gene therapy is an emerging and promising field that can change the trajectory of how ocular diseases will be treated in the future.

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Ocular Gene Therapy: A Literature Review With Focus on Current Clinical Trials - Cureus

Voretigene neparvovec (Luxturna, Spark Therapeutics) is the first causal treatment for biallelic RPE65 mutationassociated retinal disease, which regularly progresses to legal blindness. The one-time gene therapy aims to deliver the correct coding sequence of the human RPE65 gene to the retinal pigment epithelium and is performed via subretinal injection following vitrectomy.

The therapy was approved by both the European Medicines Agency (in 2018) and US Food and Drug Administration (in 2017) after data from the supporting pivotal phase 3 study revealed statistically significant functional vision improvement in patients in terms of increased light sensitivity. The findings also showed improved ability to navigate a mobility course at different levels of environmental illumination.

New gene therapies such as these raise the hope of treating a previously incurable disease with a favorable adverse effect profile. However, as with any new therapeutic product, there are limited real-world data, so it is natural that uncertainties regarding the durability and benefit-risk ratio exist.

Recent reports of retinal atrophy development in the postoperative course of the disease have led to concerns that voretigene neparvovec could lead to potentially devastating consequences in the long-term. It is therefore necessary to closely follow-up treated patients with multimodal imaging approaches in order to assess retinal morphology and gain further knowledge on the factors possibly contributing to atrophy development.

RPE65 mutationassociated disease

The RPE65 gene encodes a key enzyme in the retinoid cycle and is responsible for the regeneration of the light-sensitive component of rhodopsin, our visual purple.1 When light enters the eye, it hits the photoreceptors in the retina leading to a conversion of the light signal into a chemical signal.2

This so-called photoisomerization of the vitamin A derivative 11-cis-retinal (to all-trans-retinal) cannot take place unless there is sufficient functional 11-cis-retinal available. Because 11-cis-retinal decays after initiation of the visual process, it must be perpetually regenerated by specific metabolic processes in the retinal pigment epithelium to initiate and maintain the visual process.3

Mutations in the RPE65 gene result in deficiency or severely functionally impaired isomerohydrolase activity, causing a severe rod-cone dystrophy.4 The clinical courses of RPE65-associated retinal dystrophy are thought to result from different residual activity of the enzyme.

Clinically, the 2 most common forms of RPE65-related retinal disease are Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy. In both forms, visual impairment is first noticed at birth and during the first years of life, respectively, and worsens over time, eventually leading to complete blindness.5

LCA is considered the most severe form of early childhood blindness and was first described by Theodor Leber in 1869.6 Affected infants usually show lack of eye contact and nystagmus and/or present with conspicuous pressing of their eyeballs with fingers, fists, or toys (oculo-digital phenomenon).

Parents may report that their child frequently trips over objects or bumps into obstacles, especially in dim light. Early-onset severe retinal dystrophy that manifests after infancy also has a very poor prognosis and, like LCA, usually leads to blindness in the third to fifth decade of life.

To date, it is known that LCA can be caused not only by alterations in the RPE65 gene, but also by mutations in a further 24 genes (see: https://sph.uth.edu/retnet/sum-dis.htm#A-genes). However, mutations in the RPE65 gene might also manifest in the form of retinopathia pigmentosa (RP20).7

In the subtype of RP20, a noticeable deterioration of visual acuity usually occurs in young adulthood or adolescence while concentric loss of visual field is already advanced.7 Common to all forms of RPE65 mutationassociated retinal disease is a pronounced night blindness, which presents as one of the earliest and most characteristic symptoms of the disease, and a progressive, irreversible retinal degeneration.

The night blindness can be explained by the functional impairment of the rods, which are already affected at the earliest disease stages. Rods, unlike cones, are completely dependent on 11-cis-retinal regeneration through the retinoid cycle of the retinal pigment epithelium. Cones are less affected in early stages of the disease because they can rely on 11-cis-retinal from other sources, such as Mller cells, which explains their better function in early disease stages.8-10

Gene therapy surgery and mechanism of action

Voretigene neparvovec consists of the capsid of an adeno-associated viral vector serotype 2 (AAV2) containing a correct coding sequence (cDNA) of the human RPE65 gene and regulatory elements.11 This is provided in the form of frozen concentrate, which must be prepared into a vector solution by trained personnel.

Subsequently, the therapy is provided in a syringe containing the vector solution that must be applied within 4 hours after preparation. Following vitrectomy, delivery of the vector solution is performed by using a small injection cannula by placing it onto the retina and applying slight pressure to create a retinotomy through which the fluid can pass into the subretinal space (see Figure 1).

The injection may be performed manually with the help of an assisting surgeon or using a foot pedalcontrolled injection device. Patients receive a single dose of 1.5 x 1011 vector genomes of voretigene neparvovec in each eye; the intended target volume is 300 l.

The injection forms 1 or more fluid-filled bubbles under the retina (blebs). These are reabsorbed within 24 to 48 hours after subretinal delivery, as the drug is taken up by the target cells, the retinal pigment epithelium. Uptake into the target cells is receptor mediated.

Once in the nucleus, the single-stranded DNA is transcribed into double-stranded DNA, and the mRNA is subsequently translated in the cytosol into the functional protein, the enzyme isomerohydrolase (illustrated in Figure 2).

Reports of atrophy development following administration

Data from the clinical studies leading to approval of voretigene neparvovec showed that there are certain risks associated with the gene therapy procedure. However, most of the treatment-related adverse events were transient and mild. These included elevated IOP (18%), cataract formation (18%), ocular inflammation (8%), retinal tears (8%), dellen (8%), and retinal deposits (8%).12,13

The previously undescribed complication of chorioretinal atrophy development following treatment with voretigene neparvovec was recently reported by Gange and colleagues.14 Eighteen eyes of 10 patients developed perifoveal chorioretinal atrophy; in 80% of the cases this was seen bilaterally.

Atrophy was first identifiable anywhere between 1 week and 1 year postoperatively at an average of 4.7 months after treatment (follow-up period, 4-18 months). In 10 eyes, the atrophy occurred within and outside the area of the subretinal bleb, whereas in 7 eyes, it formed exclusively within the blebs area.

One eye showed atrophy only outside the bleb area. Despite atrophy development, functional results remained stable or improved in the majority of patients. Twelve of 18 eyes showed improved visual acuity (VA), whereas in 3 of the eyes VA did not change.

VA decreased in a further 3 eyes. After statistical analysis, no significant change in mean VA was found pre- versus postoperatively (P = .45). Although all 13 eyes with reliable Goldmann visual field tests showed improvement (expansion or gain of isopters), paracentral scotomas caused by the atrophy were seen in 3 eyes.

Another recent publication reported progressive atrophy development in 13 eyes of 8 patients.15 All eyes developed atrophy within the bleb area and 3 patients additionally developed atrophic changes outside the bleb.

The mean duration of the patients follow-up period was 15.3 months (range, 6-27). First signs of developing atrophy as detected by reduced autofluorescence were identifiable in 5 of 8 eyes as early as 2 weeks after treatment, which represented the earliest postoperative visit.

At month 3 following therapy, all 13 eyes showed areas of retinal atrophy. Notably, the atrophy area enlarged over time and in 6 of 7 eyes with existing follow-up data after 1 year, atrophy development progressed even after 1 year. Functional improvement shown by increased light sensitivity and perimetry seemed to be overall stable over the observational period despite atrophy development.

What could be the cause of atrophy?

Possible explanations for the development of atrophy include immune reactions against the vector genome (eg, promotor sequence as the CAG promotor in voretigene neparvovec, the expressed transgene, or manufacturing-related impurities) or against the capsid. Manufacturing-related factors could also include subtle deviations in the preparation of the gene therapy shortly before therapy administration at the respective treatment center.

Surgical factors may also play an important role. Mechanical stress and/or damage at the injection site as well as shear stress within the bleb may directly lead to damage of the retina or trigger deleterious stress responses. This may be particularly relevant in the setting of RPE65-related retinal disease and other inherited retinal dystrophies in which dystrophic changes and a more fragile, thinned retina may predispose to damage.

Patient-related factors should be considered as well. Age, gender, stage of disease, and immune status of the individual patient could influence the functional outcome and morphological state of the retina after treatment.

Conclusion

Early detection of inherited retinal diseases is becoming increasingly important, as earlier diagnoses enable more timely initiations of therapy and thus potentially lead to better prognoses for affected patients. Symptoms such as increased sensitivity to light (photophobia), night blindness, or nystagmus may indicate an inherited retinal disease and require a thorough ophthalmological work-up within a specialized ophthalmogenetic department.

If there is reasonable suspicion, molecular genetic testing should be carried out. This is crucial to determine whether therapy with voretigene neparvovec is applicable. Gene therapy with this product must only be performed in individuals with confirmed biallelic RPE65 mutationassociated retinal dystrophy and sufficient viable retinal cells.

Limited real-world data initially confirmed the tolerable safety profile seen in marketing authorization trials.16 However, the recent reports of progressive atrophy development following therapy are undoubtedly concerning.

In summary, currently available data are insufficient to draw definite conclusions about the causes of atrophy development and their functional consequences in the long-term. Experiences of other treatment centers, including reports of the exact surgical procedure and patient details as well as longer follow-up periods, are necessary to reach a more accurate picture on possible long-term effects of the therapy. This could have important implications for the selection of patients and will help in predicting the expectable treatment benefit for eligible patients.

Maximilian J. Gerhardt, MD

Stylianos Michalakis, PhD

Gnther Rudolph, MD

Claudia Priglinger, MD

Siegfried Priglinger, MD*

E: siegfried.priglinger@med.uni-muenchen.de

Drs Gerhardt, Michalakis, Rudolph, Priglinger, and Priglinger are based at the Department of Ophthalmology, Ludwig-Maximilians-University Munich in Germany.

*Corresponding author

References

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