Applied StemCell Announces the Expansion of its cGMP Manufacturing Facility to Support Cell and Gene Therapy – Business Wire

MILPITAS, Calif.--(BUSINESS WIRE)--Applied StemCell, Inc. (ASC), a leading cell and gene therapy CRO/CDMO focused on supporting the research community and biotechnology industry for their needs in developing and manufacturing cell and gene products, today announced the expansion of its Current Good Manufacturing (cGMP) facility. ASC has successfully carried out cell banking and product manufacturing projects in its current cGMP suite and is now set on building 4 additional cGMP cleanrooms, cryo-storage space, and a process development and QC/QA space. The expansion of the facility will increase its cell banking and cell product manufacturing capacity and allow ASCs team of experts to work simultaneously on multiple manufacturing projects such as iPSC generation, gene editing, differentiation, and cell bank manufacturing for safe and efficacious therapeutic products.

We are very excited to move forward with the expansion of our cGMP facility, said Dr. David Lee, Ph.D., Head of GMP and Quality. Our team has been working closely with our clients to ensure delivery of high-quality clinical grade products. We thank our customers for their support and trust. With the addition of 4 cGMP cleanrooms, we will be able to assist a greater number of researchers focused on cell and gene therapy.

President and CEO, Dr. Ruby Yanru Chen-Tsai, Ph.D. stated, We are committed to becoming a CDMO leader to support regenerative medicine and cell/gene therapy development and manufacturing. We aim to expand our bio-manufacturing capacity to meet the fast-growing demand in the cell and gene therapy industry. Our unique platform of GMP-grade allogeneic iPSC and TARGATTTM gene editing technology provides our partners great advantages, including shorter manufacturing timelines, non-viral gene editing, and genomic stability and safety.

Construction will begin within the next month, and the company has already begun the staff hiring process. ASC hopes to have the expansion completed and a team built that will be ready to take on as much as 4 times more new projects early next year.

About Applied StemCell, Inc.

ASC has a Drug Manufacturing License from the California Department of Public Health, Food and Drug Branch (FDB). It has a Quality Management System (ISO 13485 certified) and established cGMP-compliant protocols for cell banking and manufacturing, iPSC generation, genome editing, iPSC differentiation, and cell product manufacturing. With over 13 years of gene-editing and stem cell expertise, ASC offers comprehensive and customized cell and gene CRO/CDMO solutions. Its core iPSC and genome editing (CRISPR and TARGATTTM) technologies, facilitate site-specific, large cargo (up to 20kb) transgene integration and the development of allogenic cell products.

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Applied StemCell Announces the Expansion of its cGMP Manufacturing Facility to Support Cell and Gene Therapy - Business Wire

India Gene Therapy Market Research Report 2022: Prospects, Trends, Market Size and Forecasts to 2028 – ResearchAndMarkets.com – Business Wire

DUBLIN--(BUSINESS WIRE)--The "India Gene Therapy Market: Prospects, Trends Analysis, Market Size and Forecasts up to 2028" report has been added to ResearchAndMarkets.com's offering.

The country research report on India gene therapy market is a customer intelligence and competitive study of the India market. Moreover, the report provides deep insights into demand forecasts, market trends, and, micro and macro indicators in the India market.

Also, factors that are driving and restraining the gene therapy market are highlighted in the study. This is an in-depth business intelligence report based on qualitative and quantitative parameters of the market.

Additionally, this report provides readers with market insights and a detailed analysis of market segments to possible micro levels. The companies and dealers/distributors profiled in the report include manufacturers & suppliers of the gene therapy market in India.

Highlights of the Report

The report provides detailed insights into:

The report answers questions such as:

Segments Covered

Segmentation Based on Type

Segmentation Based on Application

Segmentation Based on Vector Type

For more information about this report visit https://www.researchandmarkets.com/r/v4ek75

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India Gene Therapy Market Research Report 2022: Prospects, Trends, Market Size and Forecasts to 2028 - ResearchAndMarkets.com - Business Wire

Walk Again Or Stop Blindness. How Gene Therapy Is Revolutionizing Medicine – Nation World News

Its an impressive thing, an absolute revolution for medicine, he says. Osvaldo Podhajesarmolecular biologist who integrates Leloir Institute who with their team are almost the only ones who investigate gene treatment in Argentina. These treatments are based on the concept of being able to modify a cell at the genetic level so that a disease can be reversed. Some examples that show how disruptive these treatments are are patients. Spinal Muscular Atrophy (SMA) those who sit or walk, those who progress to blindness from Alzheimers disease Labour and regained vision or those that were somehow cured leukemia, In that league, where science thins some fictional stories, it is this type of therapy at play that represents a unique window toward a new opportunity for thousands of people.

One of the possible techniques for performing this type of therapy is described by Hernan Martinoboss Scientific researcher from the University Hospital of Australias Pediatric Neurology and the Argentine Federation of Rare Diseases (Fedepof)Genetically modified is to administer genetic material to the patient by means of a viral vector. This modified virus, which also removed the possibility of being pathogenic, is the one that enters the cells and corrects the error.

What three criminal lines can child death investigators pursue in Crdoba?

for its part, Susanna Baldinimedical director of the Argentine Chamber of Medicinal Specialties (Caeme)who, among other topics, talked about gene therapies at the first meeting of media and pharmawhich took place in Mendoza, in which they participated Country, show that the nucleus of the cell contains chromosomes, which are formed by genes. With each chromosome having two pairs, it is possible that one or both are mutated. Dominant diseases require only one copy to be abnormal to develop in the individual, whereas recessive diseases require both copies to be mutated. And those errors or mutations are what this type of therapy tries to correct.

A little history

Podhajaser Explains that the first clinical trials of gene therapy took place in 1990 and involved genetically modifying the T lymphocytes of a girl who suffered from an immunodeficiency linked to the ADA (adenosine deaminase) gene. In boys who suffer from this disease, their immune system does not work properly and they have to stay in isolation. Since then, thousands of clinical studies have been conducted in this discipline, used in congenital metabolic diseases (where the mutated gene is known to be unable to produce normal proteins) and in more complex diseases such as cancer or neurodegenerative diseases. . ,

,Gene therapy has made remarkable progress And these children with mutations in the ADA gene can have gene therapy and can now lead normal lives with their reorganized immune systems. But advances in gene therapy have occurred not only in this disease in particular, but also extend to retinopathy, where people with blindness have regained their vision as if Leber congenital amaurosis. In this case, the RP65 gene is directly delivered to the retina. or with friends spinal muscular atrophy One who cannot sit can do so again after receiving specific gene therapy of the mutated gene which is also administered using viral vectors, he details. Podhajaser,

amartino Recalls a case of a patient in the late 1990s who was treated for a disease OTC, which had a very severe immune reaction to the vector and died. This delayed many other research related to gene therapy. However, later studies continued and today the results are generally very successful. Of course, he claims amartinoThere is still not enough time to know if these treatments will have any effect for long-term use.

two types of gene therapy

On the one hand, this description amartinothere are in vivo therapy, In this type of therapy, the viral vector that transfers the gene can be applied directly to the organ or tissue where the disease is most affected.

Instead, in ex vivo Stem cells are taken from the patient, we modify them and we insert a new gene into them. Then we re-infect the previously modified cells. Its Like an Autotransplant, For that you have to first give him chemo and remove all his white blood cells. Whether one type of therapy or the other is used will depend on the patients disease, although there are diseases for which both methods are investigated, says the expert.

An example of an ex vivo therapy is CAR-T. is used, It is a cellular gene therapy where cells are taken from the patient and they are genetically manipulated so that they can attack the malignant cells. So the patient kills his own cancer. For now this type of treatment is mainly used for certain types of leukemia., he argues baldini,

Podhajaser warns that the use of car-t It is a treatment that, although it is already used, is very complex. An appropriate laboratory is required to modify these cells with the gene of interest. After modification, the cells are kept in the laboratory for some time and reintroduced to the patient. The patient must be close to that laboratory and the cells cannot be shipped from Argentina to the United States because they will not arrive properly.

another problem of car-tadd Podhajaser Like conventional cancer therapy, the tumor has resistance over time. CAR-Ts are usually directed against a specific protein that they recognize and use to attack the malignant cell. Unfortunately, tumors can recur from cells that do not express this protein and thus survive treatment.

The third drawback is that car-t They do not work as a sole treatment in solid tumors, which are the most frequent tumors. And the reasons are simple: they work so well in hematopoietic tumors because they are cells that do not form a compact tumor tissue, unlike most cancers. And CAR-T just cant enter the tumor, he explains. Podhajaser,

Innovative, but too expensive

One of the issues with these treatments is cost. Millions of dollars are being invested in research and development for hundreds of rare diseases, but this high level of investment is inevitably going to make the treatments very expensive, he laments. express. amartino,

In Argentina, there was a case demonstrating the complexity of obtaining sufficient funding for this type of treatment. Emma, the child who suffered from SMA type 2 and required US$2,100,000 worth of medication from the Novartis laboratory. In order to increase that amount, the influential person Santiago Marata launched the campaign Everyone with Emmita.

,Gene therapy far too expensive, on the order of hundreds of thousands of dollars. Many of the accepted gene therapies either cure a person with a previously incurable disease, or significantly increase their quality of life. To address the payment for these treatments, what is being achieved is negotiations between developing companies and states, because being rare diseases, there are not so many patients who need these treatments, he says. . Podhajaser,

with your colleague, baldini Gives the example of Spain, where there is a shared risk scheme between companies and the state. If they give treatment to the patient and it is not successful, they do not pay for the said treatment.

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Walk Again Or Stop Blindness. How Gene Therapy Is Revolutionizing Medicine - Nation World News

Porton Advanced and Kun Tuo Announce Strategic Partnership to Deepen Gene and Cell Therapy CDMO and Clinical Research Services – PR Newswire

SUZHOU, China, Aug. 29, 2022 /PRNewswire/ -- On August 20, 2022, Porton Advanced Solutions (hereinafter referred to as "Porton Advanced") and Kun Tuo Medical Research and Development (Beijing) Co., Ltd. (hereinafter referred to as "Kun Tuo") established a strategic partnership in gene and cell therapy R&D, manufacturing and clinical services to accelerate the development and industrialization of innovative drugs.

Through this strategic cooperation, Porton Advanced and Kun Tuo will fully leverage their strengths, client resources and professional team capabilities to deepen cooperation in gene and cell therapy R&D, manufacturing and clinical research, providing one-stop CDMO and clinical research services for innovative drug companies and cooperating to establish a high-quality gene and cell therapy industry ecosystem.

Focusing on gene and cell therapy, Porton Advanced has built CDMO platforms for plasmids, cell therapy, gene therapy, oncolytic virus, nucleic acid therapy and microbial vector based gene therapy .In the process of gene and cell therapy drug development, Porton Advanced can provide CDMO services such as IND-CMC pharmacological research and clinical sample GMP production. Up to now, the cell therapy CDMO platform houses more than 22 cell therapy IND-CMC projects, covering various cell types such as CAR-T, UCAR-T, TCR-T, TIL, CAR-MSC, CAR-NK, NK and RBC.

As a clinical research organization (CRO) specially established by IQVIA for the Chinese market, Kun Tuo inherits its refined quality management system and standards, coupled with abundant clinical resources, offering high quality CRO services throughout IND to NDA. Since its establishment in 2011, Kun Tuo has provided over 1,000 clinical study services for multiple renowned pharmaceutical companies at home and abroad.

Dr. Wang Yangzhou, CEO of Porton Advanced, said, "We are very pleased to announce that we entered into a strategic partnership with Kun Tuo. Porton Advanced focuses on the field of gene and cell therapy and is committed to establishing a global, end-to-end CDMO service platform, while Kun Tuo delves into clinical research services and has very rich clinical resources as well as a highly professional clinical research & reporting team with strict quality standards. Through our in-depth cooperation and integration of resources and advantages, both parties will help to promote the construction of the gene and cell therapy industry ecosystem and empower more new drugs to scale new level based on an integrated drug service platform, thereby allowing enabling public's early access to good medicines."

Wang Ling, General Manager of Kun Tuo, said, "Cell and gene therapy is a new generation of breakthrough therapies after small molecule and large molecule targeted therapies, and it is also one of the most promising sectors of biopharmaceuticals at present. As a full-service CRO focusing on local clinical trials in China, Kun Tuo has built a dedicated team to conduct clinical trials of cell therapy-related products since 2018, and has been taking the lead in the field of cell and gene therapy. We also provide services from clinical development to commercialization strategy research for our clients with the commercialization team of our group company IQVIA, so that the products can serve patients faster and better. Porton Advanced is a well-known CDMO company d with professional and rich experience in drug development and manufacturing in the industry We hope that by joining hands with Porton Advanced, we can combine the expertise and strengths of both sides to provide domestic biopharmaceutical companies with a one-stop solution from drug R&D, clinical trials to commercialization."

About Porton Advanced SolutionsEstablished in Suzhou Industrial Park in December 2018, by its parent company Porton Pharma Solutions Ltd. (Stock Code: 300363), Porton Advanced has built a CDMO platform integrating plasmid, cell therapy, gene therapy, oncolytic virus, nucleic acid therapy and microbial vectors used for gene therapy (MVGTs), providing end-to-end services from cell banking, process development and analytical development, cGMP production to final Fill and Finish , investigator-initiated clinical trials (IIT), investigational new drugs (IND), clinical trials to commercial production. Porton Advanced is dedicated to support sponsors advance their GCT drug development and market launches.

Porton Advanced focuses solely on gene and cell therapy services. Built on the professional experience of its cohort of world-class professionals, as well as on the successes of its parent company, Porton Advanced insists on "Customer First" and the tenet of "Compliance, Expertise, Focus, Open Collaboration". With its key focus on protecting IP for its sponsors, through its comprehensive project management and quality systems, Porton Advanced strives to bring gene and cell therapy products to the clinic and the market through its quality CDMO services, and help bring the best medicine to the public sooner.

About KunTuoKunTuo, as a full-service Contract Research Organization (CRO) specially set up in China by IQVIA (a wholly owned subsidiary of IQVIA) and with a team of nearly 1000 employees, is dedicated to provide high-quality and reliable clinical research services for Pharmaceutical and Medical Device & Diagnostic (MDD) enterprises. Since its establishment in 2011, Kuntuo has provided more than 1000 clinical research services for many well-known pharmaceutical and device companies in China and abroad and now has accumulated rich clinical resources, including more than 10,000 departments' enrollment data and nearly 500 institutions'/departments' process information. Kuntuo inherits IQVIA's sound quality management system and quality standards, and provides biomedical enterprises with higher quality and more responsive service model from IND to NDA through the application and optimization of IQVIA's global operation experience and expertise.

SOURCE Porton Advanced Solutions

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Porton Advanced and Kun Tuo Announce Strategic Partnership to Deepen Gene and Cell Therapy CDMO and Clinical Research Services - PR Newswire

Therapeutic Solutions International Develops Gene Silencing Therapy for Acute Respiratory Distress Syndrome – BioSpace

Aug. 29, 2022 13:00 UTC

Company Continues Accelerated Development of Candidate Pipeline and Patent Portfolio in Respiratory Medicine Space as Phase III Trial Proceeds

ELK CITY, Idaho--(BUSINESS WIRE)-- Therapeutic Solutions International announced today data and filing of a patent covering the use of gene silencing in treatment of Acute Respiratory Distress Syndrome (ARDS), a leading cause of death in emergency rooms.

The Company currently is running a Phase III trial treating COVID-19 induced ARDS but has requested permission from the FDA to expand to ARDS caused by other precipitating factors.

The new data demonstrates feasibility of selectively silencing genes in the lung associated with mortality caused by ARDS, as well as a potent survival advantage in treated versus untreated mice. An approximately 70% reduction in mortality was observed in mice receiving siRNA specifically towards the target genes as compared to mice receiving scrambled siRNA in a TLR4 agonist induced model of ARDS.

The Company plans to continue development of this approach, which is attempted to synergize with the current regenerative medicine programs currently underway.

We are committed to making a significant impact in the lives of patients with ARDS. As part of that commitment, we need to constantly push the limits of medicine and science, said Dr. James Veltmeyer, Chief Medical Officer of the Company. Having previously demonstrated our ability to initiate and run clinical trials, as well as obtain Emergency IND approval, we are confident that we are in the position to accelerate this and other therapeutics in the area of respiratory medicine for which no curative therapeutic approaches exist.

The value of a biotechnology company is in its programs and intellectual property. As our ongoing Phase III continues, our team is brilliantly leveraging this waiting period to continually advance our science. This is what patients and investors count on use to do, said Timothy Dixon, President and CEO of the Company.

About Therapeutic Solutions International, Inc.

Therapeutic Solutions International is focused on immune modulation for the treatment of several specific diseases. The Company's corporate website is http://www.therapeuticsolutionsint.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220829005264/en/

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Therapeutic Solutions International Develops Gene Silencing Therapy for Acute Respiratory Distress Syndrome - BioSpace

Gene therapies for lung cancer identified by international team of scientists – Labiotech.eu

Gene therapies for lung cancer can be found by CRISPR genome editing technology, an international team of scientists have discovered.

CRISPR genome-editing is a powerful tool that gives scientists a cheap and easy way to find and alter a specific piece of DNA within a cell the cut and paste of the biological world.

The research team led by associate professor Rory Johnson of UCD Conway Institute published the study findings in the current issue of the scientific journal,Cell Genomics.

Lung cancer is the leading cause of cancer mortality. The researchers say the work set out to create new routes to developing non-small cell lung cancer therapies based on RNA therapeutics (RNATX). RNATX have recently emerged as promising new strategy for developing therapies against common diseases.

Johnson said: The biggest hurdle is identifying the optimal gene targets for RNATX in a given disease. This project achieves that by combining CRISPR genome-editing with lncRNAs to select the most promising lncRNA targets for therapy.

Using the CRISPR tool, the team initially identified 80 possible lncRNA targets that are active in NSCLC. Further screening homed in on two potential drug targets that have been named as Cancer Hallmarks in Lung LncRNA (CHiLL) 1 and GCAWKR.

These targets will now be further investigated.

Lung cancer is a critical unmet medical need. It is the greatest cancer killer in Ireland and worldwide. Present therapies fail to effectively treat most patients, leading to a poor 5-year survival that has improved little over past decades.

Professor Helen Roche, director at UCD Conway Institute said: These findings offer a widely applicable strategy to discover new targets for RNATX in virtually any cancer. I want to congratulate Rory and his colleagues worldwide on this work.

The team plan to further develop the candidate gene targets for preclinical testing with a view to moving into clinical trials if successful.

They will also look to further improve screening techniques to discover better targets, more rapidly and cheaply, and in other cancer types.

The study was initiated by Johnson group while located at the University of Bern, and completed in University College Dublin, funded by a Science Foundation Ireland (SFI) Future Research Leaders grant to Rory Johnson.

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Orchard Therapeutics Announces Multiple Presentations at 2022 SSIEM Annual Symposium Highlighting Neurometabolic Disease Portfolio – Yahoo Finance

Orchard Therapeutics (Europe) Limited

BOSTON and LONDON, Aug. 29, 2022 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, today announced seven presentations from across its neurometabolic portfolio will be featured at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium, taking place from August 30 to September 2, 2022, in Freiburg, Germany.

Featured presentations include an oral presentation on Libmeldy (atidarsagene autotemcel) from clinical development through approval by the European Commission and treatment of the first patients in a commercial setting in Europe, several accepted abstracts highlighting newborn screening efforts to support the timely and accurate diagnosis of metachromatic leukodystrophy (MLD), as well as an encore clinical data presentation from the companys investigational hematopoietic stem cell (HSC) gene therapy OTL-203 for MPS-IH.

The oral presentation details are as follows:

Title: LC-MSMS sulfatides measurement in dried blood spots for the diagnosis of metachromatic leukodystrophy Date/Time: Wednesday, August 31 at 3:30 p.m. CEST Type: Parallel Session 2A Session: Mechanisms and Markers in Lysosomal Disorders Lead Author: Dr. Magali Pettazzoni Abstract #: 2378

Title: From academic clinical development to an approved commercial drug administered in multiple highly specialised centres: arsa-cel, a lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy (MLD) Date/Time: Thursday, September 1 at 12:15 p.m. CEST Type: Parallel Session 3A Session: Gene Therapy Clinical Trials Lead Author: Dr. Francesca Fumagalli Abstract #: 2118

Title: Hematopoietic stem & progenitor cell gene therapy for Hurler syndrome: interim clinical results and extensive metabolic correction Date/Time: Thursday, September 1 at 2:30 p.m. CEST Type: Parallel Session 3A Session: Gene Therapy Clinical Trials Lead Author: Dr. Francesca Tucci Abstract #: 2040

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The poster presentation details are as follows:

Title: Blood spot hexadecanoyl sulphatide concentration in metachromatic leukodystrophy and age-matched, ARSA pseudodeficiency, and unaffected controls Lead Author: Dr. Heather Brown Abstract #: 2810

About Libmeldy / OTL-200Libmeldy (atidarsagene autotemcel), also known as OTL-200, has been approved by the European Commission for the treatment of MLD in eligible early-onset patients characterized by biallelic mutations in the ARSA gene leading to a reduction of the ARSA enzymatic activity in children with i) late infantile or early juvenile forms, without clinical manifestations of the disease, or ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Libmeldy is the first therapy approved for eligible patients with early-onset MLD.

The most common adverse reaction attributed to treatment with Libmeldy was the occurrence of anti-ARSA antibodies. In addition to the risks associated with the gene therapy, treatment with Libmeldy is preceded by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative conditioning, which carry their own risks. During the clinical studies of Libmeldy, the safety profiles of these interventions were consistent with their known safety and tolerability.

For more information about Libmeldy, please see the Summary of Product Characteristics (SmPC) available on the EMA website.

Libmeldy is approved in the European Union, UK, Iceland, Liechtenstein and Norway. OTL-200 is an investigational therapy in the U.S.

Libmeldy was developed in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy.

About Orchard TherapeuticsAt Orchard Therapeutics, our vision is to end the devastation caused by genetic and other severe diseases. We aim to do this by discovering, developing and commercializing new treatments that tap into the curative potential of hematopoietic stem cell (HSC) gene therapy. In this approach, a patients own blood stem cells are genetically modified outside of the body and then reinserted, with the goal of correcting the underlying cause of disease in a single treatment.

In 2018, the company acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Today, Orchard is advancing a pipeline spanning pre-clinical, clinical and commercial stage HSC gene therapies designed to address serious diseases where the burden is immense for patients, families and society and current treatment options are limited or do not exist.

Orchard has its global headquarters inLondonandU.S. headquarters inBoston. For more information, please visitwww.orchard-tx.com, and follow us onTwitterandLinkedIn.

Availability of Other Information About OrchardInvestors and others should note that Orchard communicates with its investors and the public using the company website (www.orchard-tx.com), the investor relations website (ir.orchard-tx.com), and on social media (TwitterandLinkedIn), including but not limited to investor presentations and investor fact sheets,U.S. Securities and Exchange Commissionfilings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

Forward-looking StatementsThis press release contains forward-looking statements, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards most recent annual or quarterly report filed with the U.S. Securities and Exchange Commission (SEC), as well as subsequent filings and reports filed with the SEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

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Orchard Therapeutics Announces Multiple Presentations at 2022 SSIEM Annual Symposium Highlighting Neurometabolic Disease Portfolio - Yahoo Finance

BioForest is Breaking Out with Innovation, Talent and Investment – BioSpace

Companies like Sana Biotechnology, Umoja Biopharma and Sonoma Biotherapeutics are heeding the call from the Tacoma mountains, making the BioForest region of Washington and Oregon a lucrative landing ground for biotech innovators. And if the rumors are to be believed, there could soon be a major player moving in.

Seattle, in particular, is a bastion for one of biopharmas hottest spaces cell and gene therapy.

You have a big focus on cell and gene therapies because you have the Hutch, which is really where the first cell therapy was developed, Andy Scharenberg, M.D., co-founder and CEO of Seattle-based Umoja told BioSpace. Scharenberg was referring to the storied Fred Hutchinson Cancer Research Center where bone marrow transplant pioneer Dr. E. Donnall Thomas discovered the potential for the human immune system to eliminate cancer.

Along with Umoja, Sana and Affini-T Therapeutics, both based in Seattle, are continuing this work. Umojas approach aims to re-engineer a patients immune system in vivo to attack and destroy both hematologic and solid organ-based tumors. Sana is a cell and gene therapy hybrid with a cloaking technology that works to overcome the immune barriers of allogeneic cells. Affini-T, launched by researchers at the Hutch, is pioneering engineered TCR T cell therapies with synthetic biology and gene editing enhancements to target oncogenic driver mutations.

Meanwhile, in December 2021, Seattle-based Tune Therapeutics announced its entrance into the sizzling epigenome editing space. This emerging field also consists of Omega Therapeutics and the brand new Epic Bio.

While Seattle gets the most attention, just to the south, Oregon is home to Sparrow Pharmaceuticals, NemaMetrix and Aronora, along with a host of scientific tools manufacturers including Araceli Biosciences and Grace Bio-Labs.

An Elite Talent Pool

BioForest-based companies are able to draw elite scientific talent from the Hutch as well as the University of Washington where Affini-T scientific co-founder Phil Greenberg maintains a teaching position. The Oregon State Universitys Center for Genome Research and Biocomputing offers another plentiful talent pool.

With established companies like Seagen in the region, there is also an ecosystem to provide management talent, Scharenberg said, noting that building a biotech requires good management.

Those factors, along with a relative affordability edge over the principle Biotech Bay and Genetown hubs have made Seattle a great place to build new biotechs, he said. You're seeing that with an increasing amount of startup activity, and also the continued capacity to grow those into at least the mid-cap range.

Seagen, Scharenberg said, is an example of a biotech that's completely homegrown - just an absolutely fantastic success - and has spawned a ton of expertise in how you grow and operate a pharmaceutical company at every stage. People have spun out of that to all over the Seattle area.

BioForest is also just that, a forest, and that appeals to the current generation of biotech talent, Scharenberg said.

There is an increasing interest in doing things in the outdoors and Seattle is amazing for that. There's probably nowhere else in the country where you can drive an hour or go backcountry skiing and feel like you're practically in the wilderness. He added that the COVID-19 pandemic has possibly added to this sentiment.

These factors clearly spoke to Sonoma. The cell therapy company, which is focused on curing autoimmune and inflammatory disease, recently announced plans to build an 83,000-square-foot operations facility in Seattle. The site will be primarily dedicated to the research, development and manufacturing of novel regulatory T cell (Treg) therapies. Sonomas first target is rheumatoid arthritis, for which it is conducting IND-enabling studies.

Heidi Hagen, chief technical officer at Sonoma, told BioSpace the company expects to hire for more than 100 positions across the Seattle area.

Seattle has an established legacy of delivering many firsts in the field of cell therapy for oncology, and Sonoma Bio is leveraging these insights to deliver the next wave of innovation Tregcell therapies for autoimmune and inflammatory diseases, she said. Hagen added that Sonoma considered proximity to transportation infrastructure, talent, technology and [its] current operations when exploring prime locations for the center.

Hagen noted that the first active cell immunotherapy, Dendreon Pharmaceuticals Provenge, for prostate cancer, was developed and approved in the Seattle area. This accomplishment led to Juno Therapeutics, which was formed by former Dendreon executives and then acquired by Celgene (now BMS) for $9 billion. Juno raised a $176 million Series A in 2014, one of the largest early-stage biotech financing rounds at the time.

The Intersection of High-Tech and Biotech

The high concentration of companies like Amazon and Microsoft in the region provides an opportunity for integration of digital technology and medical science, Hagen noted. It is at this intersection of high-tech and biotech that new genetic innovations and streamlined means of medical diagnoses and product manufacturing can be achieved.

Sana President and CEO Steve Harr, M.D. told BioSpace the critical mass of talent, large companies, emerging companies, infrastructure, capital and high-quality cities in the BioForest region are converging to make Seattle a leader in important emerging areas such as cell therapy, antibody-drug conjugates and complex manufacturing.

Harr honed in on complex manufacturing in cell therapy, which he said has emerged as a core strength and differentiator of the region that is both growing and looks sustainable.

This talent, combined with a mix of large and emerging companies, has given the area the critical mass to be a sustainable life sciences hub, Harr continued. Seattles strong foundation in cell and gene therapy and oncology is what drew Sana to the area, he said.

The Future

Historically, Seattles successful biotechs have been acquired at the small- or mid-cap range, Scharenberg noted, adding that he anticipates we're going to see more and more successful biotechs that turn into operating companies, a little bit like Seagen.

What well hopefully continue to do is see companies like [Seagen] start from scratch, grow into the small- to mid-cap stage, but also eventually be successful and hang around and grow into successful commercial biotechs that gradually move into the large biotech category, he said.

Ultimately, When you have an ecosystem that can be anchored by one or two companies that are bigger like that, and then a smattering in the middle and a really active startup situation, that for me is a really healthy ecosystem, Scharenberg concluded.

According to Harr, BioForest is right on the cusp.

I am optimistic that the Seattle area has reached a critical mass that provides the momentum for inevitable success, he shared. That said, winners attract and grow the talent base and will remain critical to the regions success.

Of course, with Mercks potential acquisition of Seagen on the horizon the deal has reportedly been stalled by a disagreement over price the regions star could rise even higher. Only time will tell.

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BioForest is Breaking Out with Innovation, Talent and Investment - BioSpace

An international team sets out to cure genetic heart diseases with one shot – Freethink

Armed with a 30 million grant from the British Heart Foundation, an international team of researchers from the UK, US, and Singapore is setting their sights on curing forms of genetic heart disease using gene therapy.

Called the CureHeart Project, the team which includes researchers from Oxford, Harvard, Singapores National Heart Research Institute, and pharma multinational Bristol Myers Squibb will develop therapies for inherited heart muscle conditions, which impact millions and can cause sudden death, including in young people.

They plan to tackle the problem using two types of targeted techniques, called base editing and prime editing.

An international team of researchers wants to develop a one-shot cure for inherited heart muscle conditions.

Many of the mutations seen in these patients come down to one fateful letter in their DNA code, Christine Seidman, professor of medicine and genetics at Harvard Medical School and co-lead of CureHeart, told The Guardian.

That has raised the possibility that we could alter that one single letter and restore the code so that it is now making a normal gene, with normal function, Seidman said.

The teams work is building on successful demonstrations in animals.

Our goals are to fix the hearts, to stabilise them where they are and perhaps to revert them back to more normal function, Seidman said.

Fixing genetic heart disease: Inherited heart muscle diseases cause abnormalities in the heart, which are passed on through families.

Many different mutations can cause them, but in total, they affect one out of every 250 people around the world, Hugh Watkins, CureHearts lead investigator and the director of Oxfords British Heart Foundation Centre of Research Excellence, told The Guardian.

People of any age can fall victim to sudden heart failure and death, and there is generally a 50/50 chance of passing the problem along to their children.

But decades of genetic research and recent innovations in gene therapy have researchers believing that gene editing may be the answer and even, eventually, the cure.

After 30 years of research, we have discovered many of the genes and specific genetic faults responsible for different cardiomyopathies, and how they work, Watkins said.

Inherited heart muscle conditions impact millions of people, and can cause sudden death.

By using prime and base editing very precise tools for editing DNA the team hopes to develop an injectable cure to repair faulty heart genes, the British Heart Foundation said in a release.

We believe that we will have a gene therapy ready to start testing in clinical trials in the next five years, Watkins told The Guardian.

According to CureHeart, their genetic goals are twofold.

When the cause is a fault in one copy of a gene, which stops the healthy copy from working, they want to switch off the faulty copy; their second approach will be to edit the broken gene sequence itself, to correct it. Theyve demonstrated both methods in mouse models.

Delivering cures: To achieve those goals, the team is turning to two different precision gene editing techniques: prime editing and base editing.

Both enable researchers to edit DNA strands without completely slicing through them (unlike the earlier CRISPR techniques). Prime editing allows researchers to insert or remove certain parts of the genome more precisely, with less collateral damage and fewer errors.

Prime editors offer more targeting flexibility and greater editing precision, Broad Institute chemist David Liu told Science.

They plan to tackle the problem using two types of targeted genetic techniques, called base editing and prime editing.

Base editing which, Science reported, Lius lab invented involves even smaller edits, engineering single letters in the code.

We may be able to deliver these therapies in advance of disease, in individuals we know from genetic testing are at extraordinary risk of having disease development and progressing to heart failure, Seidman told The Guardian.

Never before have we been able to deliver cures, and that is what our project is about. We know we can do it and we aim to get started.

Wed love to hear from you! If you have a comment about this article or if you have a tip for a future Freethink story, please email us at [emailprotected]

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An international team sets out to cure genetic heart diseases with one shot - Freethink

What is the difference between sickle cells and healthy RBCs? – Medical News Today

Sickle cell disease (SCD) refers to a group of genetic conditions that affect the red blood cells (RBCs) by altering their shape. The abnormally shaped cells are unable to perform the function of healthy RBCs efficiently. As a result, a person may experience various symptoms and complications.

SCD describes a group of genetic RBC disorders that affects roughly 100,000 people in the United States. RBCs are an important component of the blood, and they are responsible for its red color. The human body produces roughly 2 million RBCs every second.

RBCs have the vital role of carrying oxygen throughout the body. If they cannot perform this role due to SCD, a person may experience various complications, including anemia, severe pain, and organ damage.

In this article, we discuss the differences between sickle cells and healthy RBCs. We also explain how these differences affect the function of sickle cells.

Sickle cells are a type of hemoglobinopathy. This term refers to conditions that alter the production or structure of hemoglobin. This iron-rich protein plays a key role in delivering oxygen around the body and provides RBCs with their shape and color.

Many different types of hemoglobin exist. The most common type in healthy RBCs is hemoglobin A (HbA). This type of hemoglobin provides RBCs with a soft, round shape that allows them to pass easily through blood vessels and deliver oxygen effectively. On average, these healthy RBCs live for 120 days before the body replaces them with new ones.

A person with SCD instead makes a different type of hemoglobin, which is known as hemoglobin S (HbS). This type of hemoglobin causes RBCs to distort into a C-shape, or the shape of a sickle. Unlike healthy RBCs, sickle cells only live for 1020 days.

The type of hemoglobin a person produces can alter the shape of their RBCs. The hemoglobin protein consists of smaller subunits, which contain two chains of alpha-globin and two chains of beta-globin. A person with SCD has a gene alteration in the HBB gene, which is present on chromosome 11.

This alteration provides the body with instructions to produce HbS instead of HbA. This change replaces a single building block of protein, known as an amino acid, in beta-globin. Specifically, it replaces glutamic acid with valine. This single change causes the RBCs to have the characteristic sickle shape.

Healthy RBCs are round and flexible, which allows them to move easily through blood vessels and transport oxygen around the body. Due to their C-shape and rigidity, sickle cells have difficulty passing through blood vessels. As they break apart easily, clump together, and stick to the walls of blood vessels, they may block the flow of oxygen-rich blood.

This clumping of red blood cells and lack of oxygen to tissue can cause severe pain, infections, and damage to the body. Doctors refer to these severe instances of pain as a sickle cell crisis. Potential complications of SCD may include:

In severe cases, SCD can result in premature death.

Everyone inherits two sets of genes that code for the production of hemoglobin one from each parent. This is similar to how people receive the genes that determine their hair and eye color. The exact type of SCD a person has depends on what combination of genes they inherit.

Statistics show that SCD genes are more common in people of African, South and Central American, Middle Eastern, Asian, Indian, and Mediterranean descent.

There are several types of SCD. The most common types include:

The treatment for SCD can involve a variety of approaches, including medications, procedures, and lifestyle changes.

The following medications can help reduce SCD complications:

Several procedures also aim to reduce the severity of SCD symptoms:

A person with SCD may be more susceptible to dangerous complications from an infection. However, they can take steps to minimize this risk. These include:

Sickle cell disease refers to a group of genetic conditions that affect the type of hemoglobin a persons body produces. Different types of hemoglobin affect both the shape and function of red blood cells. This can lead to a person experiencing a variety of symptoms and health complications.

Treatments are available to minimize the effects of sickle cell disease and encourage the production of healthy red blood cells.

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What is the difference between sickle cells and healthy RBCs? - Medical News Today

Serious side effects reported for some people treated with the huntingtin-lowering drug AMT-130, currently in clinical trials – HDBuzz

Last month, we relayed positive news from uniQures trial testing AMT-130, a gene therapy delivered via brain surgery to lower huntingtin (HTT). Data released by uniQure in June suggested AMT-130 was safe and well tolerated in the small group of people that were treated with a low dose of the drug. Now were back to provide an update on findings from the group of people treated with a higher dose of AMT-130. This new set of data shows that the higher dose of the drug may be causing serious side effects. This doesnt necessarily mean AMT-130 doesnt work and wont move forward, but it does mean that we need to take a pause, really look into what the data are telling us, and work out a safe plan to move forward for people being treated with the drug.

One advantage researchers that study Huntingtons disease (HD) have is that we know exactly what causes HD - an expansion in the HTT gene. The expanded HTT gene produces an expanded HTT message that is then processed into an expanded form of the HTT protein that causes damage in brain cells. So, in theory, reducing the presence of that expanded HTT protein could alleviate the symptoms associated with HD because it directly targets the root cause of the disease. This means that despite recent setbacks for several clinical trials designed to lower HTT levels, HTT lowering is still considered an attractive strategy for HD therapeutics by many researchers.

There are several different ways researchers are trying to lower HTT. The first horse out of the gate in the HTT lowering race were antisense oligonucleotides (ASOs). These are short sequences that bind to a specific message which then cause it to be degraded. Without the message, no protein can be produced. So while the gene remains intact, the protein is never made. This type of HTT-lowering technology is being explored by Roche with their drug tominersen that took a step back to find the right dose and patient population. Wave Life Sciences is also using ASOs to selectively lower the expanded copy of HTT with their ongoing Phase I/II trial for WVE-003, SELECT-HD.

Another way to lower HTT thats being tested in clinical trials is through splice modulators. These are drugs that change how the genetic message is edited. Like a story, every gene has a beginning, middle, and end. The end is a specific sequence that tells molecules in the cell to stop reading the code for that gene. Splice modulators work by editing the message to move that ending code up, confusing the sequence of that gene. So rather than a beginning, middle, and end, the story is just a beginning and end. The cell recognizes that this makes no sense and stops producing that protein.

HDBuzz recently wrote about the splice modulator branaplam, being tested by Novartis in the VIBRANT-HD study, for which dosing was suspended due to safety concerns. Another splice modulator, PTC-518, is being tested by PTC Therapeutics. Even though PTC-518 works in a similar way to branaplam, a head-to-head comparison of these drugs suggests they are actually quite different. So bad news for one doesnt necessarily mean there will be bad news for the other. Were still eagerly waiting for news about the PTC-518 trial!

A third way to lower HTT is through gene therapy, which is the technology being used by uniQure with AMT-130. This drug works by using a harmless virus to deliver DNA instructions that will destroy the HTT message. The HTT gene still exists in its original form, but now the cell contains a new message that will prevent the production of the HTT protein. Because the cells infected with the harmless virus contain the genetic instructions, they can make the HTT lowering message all on their own. This means AMT-130 is a one-and-done approach - deliver the therapy through a single procedure, and the cells will continue to make the instructions that allow them to lower HTT. This is both exciting and nerve-wracking. While it means only one treatment is necessary, it also means any changes are likely permanent.

To get AMT-130 directly where its needed most - the brain - its delivered using brain surgery. Because brain surgery is always risky, this trial was rolled out very slowly to be as careful as possible. After the first 2 surgeries were complete, the participants were watched to make sure there were no immediate negative effects. When everything went well, surgery for the rest of the study participants continued.

The trial testing AMT-130, HD-Gene-TRX1, is a Phase I/II designed to test safety and tolerability of the drug as well as find the right dose that will work for people with HD. Because one of the primary goals of this study was finding the right dose that will work best for people with HD, 2 groups were tested: a low dose group and a high dose group. Scientists at uniQure believe that the higher dose of the drug will not necessarily lower HTT further in each cell, but that more drug will mean that more brain cells will have their levels of HTT lowered by the same amount.

36 people in total were enrolled in uniQures AMT-130 study: 10 that received an imitation surgery that will act as the control group, a critical part of any study, and 26 people in the treatment group. Of the 26 in the treatment group, 12 were treated with a low dose of AMT-130 and 14 were in the group for the high dose. So far, 12 of those 14 have undergone surgery.

In June we got an update from uniQure about people that were treated with the low dose of AMT-130 12 months after their surgeries, which HDBuzz wrote about. In that group, the surgeries and drug were well tolerated with no major safety issues reported. uniQure shared that preliminary data indicating that HTT seemed to be lowered more in the group treated with AMT-130 than the control group. While this is exciting news because it means AMT-130 appears to be doing what we want it to do - lowering HTT - this was reported in a very small group of only 4 participants.

In early August, uniQure made an announcement about participants from the high dose group in the AMT-130 study. Three participants (out of 14) from this arm of the study were found to have severe adverse reactions by an independent safety review committee. Two people that underwent surgery in Europe reported swelling and a third person, treated at a U.S. location, reported a severe headache and related symptoms shortly after surgery. While this is very upsetting and disappointing news, importantly, all three patients have either fully or substantially recovered and have now been released from the hospital.

There are many theories as to why these patients suffered these side effects, including some form of immune response. However, there is no clear or definitive explanations just yet and we must wait for further information before jumping to conclusions.

While the safety review committee doesnt suspect the effects observed in the high-dose group of the trial are due to the drug itself, surgeries for the remaining 2 participants in this arm of the study have been halted for now. The low-dose arm is proceeding as planned and all trial particiants - in both the low- and high-dose groups - will continue to be followed for the duration of the trial. uniQure still expect to report data from the trial according to the originally planned schedule and we will be hearing further updates from the company about this trial in early 2023.

The HD community has received disappointing news from many of the HTT lowering trials now and it is easy to feel like perhaps this is not a good strategy to keep pursuing to try and treat people with HD. It is important to keep a few things in mind though as all is not lost just yet. All of these trials have suffered very different problems and we only really have theories for why they havent panned out as we hoped, all of which might be unrelated to HTT lowering itself. All of these trials are also treating people with HD who are already showing symptoms and perhaps these folks are more vulnerable to potential side effects from these drugs. Its important to note that none of these trials have given us a definitive answer as to whether HTT lowering in people with HD will improve symptoms or change the course of the disease. As the uniQure trial continues, we hope that the next data release might shed some light on this important question.

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Serious side effects reported for some people treated with the huntingtin-lowering drug AMT-130, currently in clinical trials - HDBuzz

Cell therapy weekly: Kyverna Therapeutics appoints new Senior Vice President – RegMedNet

This week: Kyverna Therapeutics appoints new Senior Vice President, Nucleus Biologics obtains ISO 13485:2016 Certification for manufacture and distribution of cell and gene therapy media, rare pediatric disease designation granted to iECUREs investigational gene editing product candidate for OTC deficiency and construction completed on Sheffield Gene Therapy Innovation and Manufacturing Centre.

The cell therapy company focusing on regenerative treatment of serious autoimmune diseases, Kyverna Therapeutics (CA, USA),has appointed Tom Van Blarcom as Senior Vice President, Head of Research. Kyvernas therapeutic platform utilizes advanced T-cell engineering and synthetic biology techniques to suppress and eliminate the autoreactive immune cells responsible for inflammatory and autoimmune diseases.

President and CEO of Kyverna, Dominic Borie stated, We are excited to welcome Tom to the Kyverna team. His broad experience in cell therapy research across a wide range of diseases will be invaluable in supporting our work developing engineered T-cell therapies for the treatment of autoimmune diseases. Toms leadership and extensive industry experience will be a critical pillar of our company as we advance our Regulatory T-cell platform and CAR-T programs to achieve our mission of bringing curative living medicines to life to free patients from the siege of autoimmune disease.

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Nucleus Biologics (CA, USA) announced that it has received an ISO 13485:2016 certification from the British Standards Institution (London, UK) for the manufacture and distribution of media for the cell and gene therapy industry. ISO 13485 is the industry standard for quality management systems regulating medical devices and associated services and ensures that the design, development and production of a product consistently fulfils customer and regulatory requirements.

David Sheehan, CEO and Founder of Nucleus Biologics acknowledged, This milestone is the result of years of effort to extend our leadership in custom cell culture media for the cell and gene therapy market. Now, therapy developers have one partner that can offer everything from formulation development support to cGMP 2,000-liter media manufacturing all governed by strict adherence to the ISO 13485 level quality system. Our history of product innovations, quality and collaborations will only expand as we help our customers speed the time from discovery to cure.

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iECURE (PA, USA) reported that the US FDA has granted rare pediatric disease designation to GTP-506 for treatment of Ornithine Transcarbamylase (OTC) deficiency, the most common urea cycle disorder. iECURE is a gene editing company developing mutation-agnostic in vivo gene insertion therapies to treat liver disorders with significant unmet need. GTP-506 is a potential single dose dual vector gene editing product candidate, designed to restore metabolic function through cleavage of the PCSK9 gene locus and insertion of a functional OTC gene into the cleavage site.

Joe Truitt, CEO of iECURE stated, Receiving Rare Pediatric Disease Designation for GTP-506 for the treatment of OTC deficiency highlights the dire need for new treatment options for this devastating pediatric disease. GTP-506 is a potentially transformative therapy for babies born with OTC deficiency and we expect to file an investigational new drug application with the FDA for our first-in-human clinical trial in mid-2023.

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The University of Sheffield (UK) announced the completion of construction for The Sheffield Gene Therapy Innovation and Manufacturing Centre (GTIMC). The state-of-the-art center will provide translational and regulatory support in conjunction with training and skills programs in good manufacturing practice. The GTIMC is one of three innovative centers in a new 18 million network funded by LifeArc (London, UK) and the Medical Research Council (London, UK), with support from the Biotechnology and Biological Sciences Research Council (Swindon, UK).

Mimoun Azzouz, Director of the GTIMC and Chair of Translational Neuroscience at the University of Sheffield stated, Sheffield has emerged as one of the leading players in cell and gene therapy and this national network of partners, facilities and training programs will allow us to stay at the cutting edge of translational discoveries for new and potentially life changing treatments. Seeing the construction work completed is an exciting milestone for the team. It brings us closer to being fully operational and able to progress new and exciting discoveries, which will benefit patients and families worldwide.

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Cell therapy weekly: Kyverna Therapeutics appoints new Senior Vice President - RegMedNet

GICELL Announces Research Collaboration with HK inno.N for next-generation CAR-NK therapy – BioSpace

- Expecting the synergies of GICELLs research competency and HK inno.Ns know-hows on development and commercialization

- GICELL to reinforce its anticancer pipeline portfolio by leveraging its proprietary manufacturing capabilities for CAR-NK development

SEOUL, South Korea--(BUSINESS WIRE)-- GICELL announced research and development collaboration for allogeneic CAR-NK candidates with HK inno.N on August 29th, 2022.

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20220829005272/en/

The companies plan to advance the development of numerous CAR-NK therapies by harnessing GICELL's outstanding research competency and HK inno.N's extensive experience in development and commercialization of anticancer therapies. As part of this agreement, the companies may open up a discussion on further developments, including clinical development and commercialization, if they succeed in discovering CAR-NK cell product candidates and producing non-clinical samples.

GICELL, pioneering novel technology for large-scale immune cell manufacturing, expects to demonstrate its technology on scalable culture under this research agreement.

In February, GICELL set a new world record in culturing highly active natural killer cells with 200 liters. The company's manufacturing technology obtained a patent registration decision in Taiwan in July, following the corresponding patent registration in Korea at the beginning of the year.

HK inno.N, a company deeply committed to the development of breakthrough therapies and biopharmaceutical products with high market value, has developed K-CAB Tablet, a new blockbuster drug, and is enjoying unbeatable shares in basic fluid and anti-hangover beverage markets. Currently, the company has established GMP facilities based on its belief in the anticancer therapeutic potential of cell and gene therapy products as a future growth engine and seeks to secure its core competitiveness by developing a wide range of pipelines.

Sung Yoo Cho, CSO and Vice President of GICELL, a global expert on CAR-NK, confidently commented, "Allogeneic NK cells developed by GICELL have joined the lead group in the CAR-NK field by avoiding NK cell exhaustion through the adjustment of binding force of cytokine receptors during the cell culture and markedly improving the efficiency of CAR gene introduction in NK cells, which are generally known as challenging for gene expression, compared to T cells."

Sung Yong Won, Head of the Bio Research Center and Managing Director of HK inno.N said, "HK inno.N is conducting research with many companies possessing technological competitiveness in cell therapy products to accelerate the development of anticancer immune cell therapy products. The company will continue to develop its promising CAR-NK pipelines through this research and development collaboration with GICELL."

GICELL and HK inno.N will co-develop CAR-NK programs with the aim of initiating the clinical phase of CAR-NK cell therapy products by 2024.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220829005272/en/

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GICELL Announces Research Collaboration with HK inno.N for next-generation CAR-NK therapy - BioSpace

Gene therapy – Mayo Clinic

Overview

Gene therapy involves altering the genes inside your body's cells in an effort to treat or stop disease.

Genes contain your DNA the code that controls much of your body's form and function, from making you grow taller to regulating your body systems. Genes that don't work properly can cause disease.

Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve your body's ability to fight disease. Gene therapy holds promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS.

Researchers are still studying how and when to use gene therapy. Currently, in the United States, gene therapy is available only as part of a clinical trial.

Gene therapy is used to correct defective genes in order to cure a disease or help your body better fight disease.

Researchers are investigating several ways to do this, including:

Gene therapy has some potential risks. A gene can't easily be inserted directly into your cells. Rather, it usually has to be delivered using a carrier, called a vector.

The most common gene therapy vectors are viruses because they can recognize certain cells and carry genetic material into the cells' genes. Researchers remove the original disease-causing genes from the viruses, replacing them with the genes needed to stop disease.

This technique presents the following risks:

The gene therapy clinical trials underway in the U.S. are closely monitored by the Food and Drug Administration and the National Institutes of Health to ensure that patient safety issues are a top priority during research.

Currently, the only way for you to receive gene therapy is to participate in a clinical trial. Clinical trials are research studies that help doctors determine whether a gene therapy approach is safe for people. They also help doctors understand the effects of gene therapy on the body.

Your specific procedure will depend on the disease you have and the type of gene therapy being used.

For example, in one type of gene therapy:

Viruses aren't the only vectors that can be used to carry altered genes into your body's cells. Other vectors being studied in clinical trials include:

The possibilities of gene therapy hold much promise. Clinical trials of gene therapy in people have shown some success in treating certain diseases, such as:

But several significant barriers stand in the way of gene therapy becoming a reliable form of treatment, including:

Gene therapy continues to be a very important and active area of research aimed at developing new, effective treatments for a variety of diseases.

Explore Mayo Clinic studies of tests and procedures to help prevent, detect, treat or manage conditions.

Dec. 29, 2017

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Gene therapy - Mayo Clinic

Document: Big Pharma exec: COVID shots are ‘gene therapy’

An Air Force medical technician draws a dose of the COVID-19 vaccine to inoculate Air Force reservists at Joint Base Lewis McChord, Washington, Sept. 12, 2021. (U.S. Air Force photo by Staff Sgt. Paolo Felicitas)

Many skeptics have contended that the mRNA-based Pfizer and Moderna COVID-19 shots are not "vaccines" but rather a form of gene therapy that poses untold risks by altering a recipient's DNA.

The federal government and health-care experts have denied that claim. But the president of Bayer's Pharmaceuticals Division is on record describing the mRNA shots as "cell and gene therapy" and acknowledging public wariness of the technology.

Bayer executive Stefan Oelrich, LifeSiteNews reported, made the statement at the World Health Summit, which took place in Berlin Oct. 24-26, drawing 6,000 people from 120 countries.

Oelrich said his company is "really taking that leap" to drive innovation "in cell and gene therapies."

"Ultimately, the mRNA vaccines are an example for that cell and gene therapy," he said.

"I always like to say: If we had surveyed two years ago in the public 'would you be willing to take a gene or cell therapy and inject it into your body?' we probably would have had a 95% refusal rate," Oelrich said.

In August, Reuters ran a "fact check" citing experts who contend that the technology in the Pfizer/BioNTech and Moderna shots are not gene therapy.

Both shots usea piece of genetic code from SARS-CoV-2 to prompt an immune response in recipients. But Dr. Adam Taylor, a virologist and researcher at Griffith University in Australia, insisted that while it's "a genetic-based therapy," it doesn't alter a person's genes.

Gene therapy, in the classical sense, involves making deliberate changes to a patients DNA in order to treat or cure them," he said. "mRNA vaccines will not enter a cells nucleus that houses your DNA genome. There is zero risk of these vaccines integrating into our own genome or altering our genetic makeup."

At the Berlin summit, the Bayer executive said that his company's "successes" over the 18 months of the pandemic "should embolden us to fully focus much more closely on access, innovation and collaboration to unleash health for all, especially as we enter, on top of everything else that is happening, a new era of science a lot of people talk about the Bio Revolution in this context."

LifeSiteNews noted that, according to the McKinsey Global Institute, the "Bio Revolution" is "a confluence of advances in biological science and accelerating development of computing, automation, and artificial intelligence [that] is fueling a new wave of innovation."

"This Bio Revolution could have significant impact on economies and our lives, from health and agriculture to consumer goods, and energy and materials."

Oelrich said Bayer also is working at reducing the populations of Third World countries, investing $400 million in "long-acting contraceptives" and partnering with the Bill and Melinda Gates Foundation on "family planning initiatives."

EDITOR'S NOTE: Last year, America's doctors, nurses and paramedics were celebrated as frontline heroes battling a fearsome new pandemic. Today, under Joe Biden, tens of thousands of these same heroes are denounced as rebels, conspiracy theorists, extremists and potential terrorists. Along with massive numbers of police, firemen, Border Patrol agents, Navy SEALs, pilots, air-traffic controllers, and countless other truly essential Americans, they're all considered so dangerous as to merit termination, their professional and personal lives turned upside down due to their decision not to be injected with the experimental COVID vaccines. Bidens tyrannical mandate threatens to cripple American society from law enforcement to airlines to commercial supply chains to hospitals. It's already happening. But the good news is that huge numbers of "yesterdays heroes" are now fighting back bravely and boldly. The whole epic showdown is laid out as never before in the sensational October issue of WND's monthly Whistleblower magazine, titled "THE GREAT AMERICAN REBELLION: 'We will not comply!' COVID-19 power grab ignites bold new era of national defiance."

Content created by the WND News Center is available for re-publication without charge to any eligible news publisher that can provide a large audience. For licensing opportunities of our original content, please contact licensing@wndnewscenter.org.

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Document: Big Pharma exec: COVID shots are 'gene therapy'

Gene & Cell Therapy FAQs | ASGCT – American Society of Gene & Cell …

For more in-depth learning, we recommend Different Approaches in our Patient Education program.

The challenges of gene and cell therapists can be divided into three broad categories based on disease, development of therapy, and funding.

Challenges based on the disease characteristics: Disease symptoms of most genetic diseases, such as Fabrys, hemophilia, cystic fibrosis, muscular dystrophy, Huntingtons, and lysosomal storage diseases are caused by distinct mutations in single genes. Other diseases with a hereditary predisposition, such as Parkinsons disease, Alzheimers disease, cancer, and dystonia may be caused by variations/mutations in several different genes combined with environmental causes. Note that there are many susceptible genes and additional mutations yet to be discovered. Gene replacement therapy for single gene defects is the most conceptually straightforward. However, even then the gene therapy agent may not equally reduce symptoms in patients with the same disease caused by different mutations, and even the samemutationcan be associated with different degrees of disease severity. Gene therapists often screen their patients to determine the type of mutation causing the disease before enrollment into a clinical trial.

The mutated gene may cause symptoms in more than one cell type. Cystic fibrosis, for example, affects lung cells and the digestive tract, so the gene therapy agent may need to replace the defective gene or compensate for its consequences in more than one tissue for maximum benefit. Alternatively, cell therapy can utilizestem cellswith the potential to mature into the multiple cell types to replace defective cells in different tissues.

In diseases like muscular dystrophy, for example, the high number of cells in muscles throughout the body that need to be corrected in order to substantially improve the symptoms makes delivery of genes and cells a challenging problem.

Some diseases, like cancer, are caused by mutations in multiple genes. Although different types of cancers have some common mutations, every tumor from a single type of cancer does not contain the same mutations. This phenomenon complicates the choice of a single gene therapy tactic and has led to the use of combination therapies and cell elimination strategies. For more information on gene and cell therapy strategies to treat cancer, please refer to the Cancer and Immunotherapy summary in the Disease Treatment section.

Disease models in animals do not completely mimic the human diseases and viralvectorsmay infect various species differently. The testing of vectors in animal models often resemble the responses obtained in humans, but the larger size of humans in comparison to rodents presents additional challenges in the efficiency of delivery and penetration of tissue.Gene therapy, cell therapy, and oligonucleotide-based therapy agents are often tested in larger animal models, including rabbit, dog, pig and nonhuman primate models. Testing human cell therapy in animal models is complicated by immune rejections. Furthermore, humans are a very heterogeneous population. Their immune responses to the vectors, altered cells, or cell therapy products may differ or be similar to results obtained in animal models.

Challenges in the development of gene and cell therapy agents: Scientific challenges include the development of gene therapy agents that express the gene in the relevant tissue at the appropriate level for the desired duration of time. There are a lot of issues in that once sentence, and while these issues are easy to state, each one requires extensive research to identify the best means of delivery, how to control sufficient levels or numbers of cells, and factors that influence duration of gene expression or cell survival. After the delivery modalities are determined, identification and engineering of a promoter and control elements (on/off switch and dimmer switch) that will produce the appropriate amount of protein in the target cell can be combined with the relevant gene. This gene cassette is engineered into a vector or introduced into thegenomeof a cell and the properties of the delivery vehicle are tested in different types of cells in tissue culture. Sometimes things go as planned and then studies can be moved onto examination in animal models. In most cases, the gene/cell therapy agent may need to be improved further by adding new control elements to obtain the desired responses in cells and animal models.

Furthermore, the response of the immune system needs to be considered based on the type of gene or cell therapy being undertaken. For example, in gene or cell therapy for cancer, one aim is to selectively boost the existing immune response to cancer cells. In contrast, to treat genetic diseases like hemophilia and cystic fibrosis the goal is for the therapeutic protein to be accepted as an addition to the patients immune system.

If the new gene is inserted into the patients cellularDNA, the intrinsic sequences surrounding the new gene can affect its expression and vice versa. Scientists are now examining short DNA segments that may insulate the new gene from surrounding control elements. Theoretically, these insulator sequences would also reduce the effect of vector control signals in the gene cassette on adjacent cellular genes. Studies are also focusing on means to target insertion of the new gene into safe areas of the genome, to avoid influence on surrounding genes and to reduce the risk of insertional mutagenesis.

Challenges of cell therapy include the harvesting of the appropriate cell populations and expansion or isolation of sufficient cells for one or multiple patients. Cell harvesting may require specific media to maintain the stem cells ability toself-renew and mature into the appropriate cells. Ideally extra cells are taken from the individual receiving therapy. Those additional cells can expand in culture and can be induced to becomepluripotent stem cells(iPS), thus allowing them to assume a wide variety of cell types and avoiding immune rejection by the patient. The long term benefit of stem cell administration requires that the cells be introduced into the correct target tissue and become established functioning cells within the tissue. Several approaches are being investigated to increase the number of stem cells that become established in the relevant tissue.

Another challenge is developing methods that allow manipulation of the stem cells outside the body while maintaining the ability of those cells to produce more cells that mature into the desired specialized cell type. They need to provide the correct number of specialized cells and maintain their normal control of growth and cell division, otherwise there is the risk that these new cells may grow into tumors.

Challenges in funding: In most fields, funding for basic or applied research for gene and cell therapy is available through the National Institutes of Health (NIH) and private foundations. These are usually sufficient to cover the preclinical studies that suggest a potential benefit from a particular gene and cell therapy. Moving into clinical trials remains a huge challenge as it requires additional funding for manufacturing of clinical grade reagents, formal toxicology studies in animals, preparation of extensive regulatory documents, and costs of clinical trials.Biotechnology companies and the NIH are trying to meet the demand for this large expenditure, but many promising therapies are slowed down by lack of funding for this critical next phase.

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Gene & Cell Therapy FAQs | ASGCT - American Society of Gene & Cell ...

Adeno-Associated Virus (AAV) as a Vector for Gene Therapy

BioDrugs. 2017; 31(4): 317334.

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

2BiStro Biotech Consulting, LLC, Bridgewater, NJ 08807 USA

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

2BiStro Biotech Consulting, LLC, Bridgewater, NJ 08807 USA

Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

There has been a resurgence in gene therapy efforts that is partly fueled by the identification and understanding of new gene delivery vectors. Adeno-associated virus (AAV) is a non-enveloped virus that can be engineered to deliver DNA to target cells, and has attracted a significant amount of attention in the field, especially in clinical-stage experimental therapeutic strategies. The ability to generate recombinant AAV particles lacking any viral genes and containing DNA sequences of interest for various therapeutic applications has thus far proven to be one of the safest strategies for gene therapies. This review will provide an overview of some important factors to consider in the use of AAV as a vector for gene therapy.

The discovery of DNA as the biomolecule of genetic inheritance and disease opened up the prospect of therapies in which mutant, damaged genes could be altered for the improvement of the human condition. The recent ability to rapidly and affordably perform human genetics on hundreds of thousands of people, and to sequence complete genomes, has resulted in an explosion of nucleic acid sequence information and has allowed us to identify the gene, or genes, that might be driving a particular disease state. If the mutant gene(s) could be fixed, or if the expression of overactive/underactive genes could be normalized, the disease could be treated at the molecular level, and, in best case scenarios, potentially be cured. This concept seems particularly true for the treatment of monogenic diseases, i.e. those diseases caused by mutations in a single gene. This seemingly simple premise has been the goal of gene therapy for over 40years.

Until relatively recently, that simple goal was very elusive as technologies to safely deliver nucleic acid cargo inside cells have lagged behind those used to identify disease-associated genes. One of the earliest approaches investigated was the use of viruses, naturally occurring biological agents that have evolved to do one thing, i.e. deliver their nucleic acid (DNA or RNA) into a host cell for replication. There are numerous viral agents that could be selected for this purpose, each with some unique attributes that would make them more or less suitable for the task, depending on the desired profile [1]. However, the undesired properties of some viral vectors, including their immunogenic profiles or their propensity to cause cancer have resulted in serious clinical adverse events and, until recently, limited their current use in the clinic to certain applications, for example, vaccines and oncolytic strategies [2]. More artificial delivery technologies, such as nanoparticles, i.e. chemical formulations meant to encapsulate the nucleic acid, protect it from degradation, and get through the cell membrane, have also achieved some levels of preclinical and clinical success. Not surprisingly, they also have encountered some unwanted safety signals that need to be better understood and controlled [3].

Adeno-associated virus (AAV) is one of the most actively investigated gene therapy vehicles. It was initially discovered as a contaminant of adenovirus preparations [4, 5], hence its name. Simply put, AAV is a protein shell surrounding and protecting a small, single-stranded DNA genome of approximately 4.8kilobases (kb). AAV belongs to the parvovirus family and is dependent on co-infection with other viruses, mainly adenoviruses, in order to replicate. Initially distinguished serologically, molecular cloning of AAV genes has identified hundreds of unique AAV strains in numerous species. Its single-stranded genome contains three genes, Rep (Replication), Cap (Capsid), and aap (Assembly). These three genes give rise to at least nine gene products through the use of three promoters, alternative translation start sites, and differential splicing. These coding sequences are flanked by inverted terminal repeats (ITRs) that are required for genome replication and packaging. The Rep gene encodes four proteins (Rep78, Rep68, Rep52, and Rep40), which are required for viral genome replication and packaging, while Cap expression gives rise to the viral capsid proteins (VP; VP1/VP2/VP3), which form the outer capsid shell that protects the viral genome, as well as being actively involved in cell binding and internalization [6]. It is estimated that the viral coat is comprised of 60 proteins arranged into an icosahedral structure with the capsid proteins in a molar ratio of 1:1:10 (VP1:VP2:VP3) [6]. The aap gene encodes the assembly-activating protein (AAP) in an alternate reading frame overlapping the cap gene. This nuclear protein is thought to provide a scaffolding function for capsid assembly [7]. While AAP is essential for nucleolar localization of VP proteins and capsid assembly in AAV2, the subnuclear localization of AAP varies among 11 other serotypes recently examined, and is nonessential in AAV4, AAV5, and AAV11 [8].

Although there is much more to the biology of wild-type AAV, much of which is not fully understood, this is not the form that is used to generate gene therapeutics. Recombinant AAV (rAAV), which lacks viral DNA, is essentially a protein-based nanoparticle engineered to traverse the cell membrane, where it can ultimately traffic and deliver its DNA cargo into the nucleus of a cell. In the absence of Rep proteins, ITR-flanked transgenes encoded within rAAV can form circular concatemers that persist as episomes in the nucleus of transduced cells [9]. Because recombinant episomal DNA does not integrate into host genomes, it will eventually be diluted over time as the cell undergoes repeated rounds of replication. This will eventually result in the loss of the transgene and transgene expression, with the rate of transgene loss dependent on the turnover rate of the transduced cell. These characteristics make rAAV ideal for certain gene therapy applications. Following is an overview of the practical considerations for the use of rAAV as a gene therapy agent, based on our current understanding of viral biology and the state of the platform. The final section provides an overview for how rAAV has been incorporated into clinical-stage gene therapy candidates, as well as the lessons learned from those studies that can be applied to future therapeutic opportunities.

The main point of consideration in the rational design of an rAAV vector is the packaging size of the expression cassette that will be placed between the two ITRs. As a starting point, it is generally accepted that anything under 5kb (including the viral ITRs) is sufficient [10]. Attempts at generating rAAV vectors exceeding packaging cassettes in excess of 5kb results in a considerable reduction in viral production yields or transgene recombination (truncations) [11]. As a result, large coding sequences, such as full-length dystrophin, will not be effectively packaged in AAV vectors. Therefore, the use of dual, overlapping vector strategies (reviewed by Chamberlain et al.) [12], should be considered in these cases. An additional consideration relates to the biology of the single-stranded AAV-delivered transgenes. After delivery to the nucleus, the single-stranded transgene needs to be converted into a double-stranded transgene, which is considered a limiting step in the onset of transgene expression [13]. An alternative is to use self-complementary AAV, in which the single-stranded packaged genome complements itself to form a double-stranded genome in the nucleus, thereby bypassing that process [13, 14]. Although the onset of expression is more rapid, the packaging capacity of the vector will be reduced to approximately 3.3kb [13, 14].

AAV2 was one of the first AAV serotypes identified and characterized, including the sequence of its genome. As a result of the detailed understanding of AAV2 biology from this early work, most rAAV vectors generated today utilize the AAV2 ITRs in their vector designs. The sequences placed between the ITRs will typically include a mammalian promoter, gene of interest, and a terminator (Fig.). In many cases, strong, constitutively active promoters are desired for high-level expression of the gene of interest. Commonly used promoters of this type include the CMV (cytomegalovirus) promoter/enhancer, EF1a (elongation factor 1a), SV40 (simian virus 40), chicken -actin and CAG (CMV, chicken -actin, rabbit -globin) [15]. All of these promoters provide constitutively active, high-level gene expression in most cell types. Some of these promoters are subject to silencing in certain cell types, therefore this consideration needs to be evaluated for each application [16]. For example, the CMV promoter has been shown to be silenced in the central nervous system (CNS) [16]. It has been observed that the chicken -actin and CAG promoters are the strongest of these constitutive promoters in most cell types; however, the CAG promoter is significantly larger than the others (1.7kb vs. 800bp for CMV), a consideration to take into account when packaging larger gene inserts [15].

Schematic representation of the basic components of a gene insert packaged inside recombinant AAV gene transfer vector. AAV adeno-associated virus, ITR inverted terminal repeat

Although many therapeutic strategies involve systemic delivery, it is often desirable to have cell- or tissue-specific expression. Likewise, for local delivery strategies, undesired systemic leakage of the AAV particle can result in transduction and expression of the gene of interest in unwanted cells or tissues. The muscle creatine kinase and desmin promoters have been used to achieve high levels of expression, specifically in skeletal muscle, whereas the -myosin heavy chain promoter can significantly restrict expression to cardiac muscle [15, 17]. Likewise, the neuron-specific enolase promoter can attain high levels of neuron-specific expression [18, 19]. Often is the case, systemic delivery of AAV results in a significant accumulation in the liver. While this may be desirable for some applications, AAV can also efficiently transduce other cells and tissues types. Thus, in order to restrict expression to only the liver, a common approach is to use the 1-antitrypsin promoter [20, 21]. Finally, there are now technologies that have the ability to generate novel, tissue-specific promoters, based on DNA regulatory element libraries [22].

Over the course of the past 1015years, much work has been done to understand the correlation between codon usage and protein expression levels. Although bacterial expression systems seem to be most affected by codon choice, there are now many examples of the effects of codon engineering on mammalian expression [23]. Many groups have developed their own codon optimization strategies, and there are many free services that can similarly provide support for codon choice. Codon usage has also been shown to contribute to tissue-specific expression, and play a role in the innate immune response to foreign DNA [24, 25]. With regard to the gene of interest, codon engineering to support maximal, tissue-specific expression should be performed.

Additionally, terminator/polyadenylation signal choices, the inclusion of post-transcriptional regulator elements and messenger RNA (mRNA) stability elements, and the presence of microRNA (miRNA) target sequence in the gene cassette can all have effects on gene expression [26]. The human factor IX 3 UTR, for example, was shown to dramatically increase factor IX expression in vivo, especially in the context of additional cis regulatory elements [27]. Likewise, synthetic miRNA target sequences have been engineered into the 3 UTR of AAV-delivered genes to make them susceptible to miRNA-122-driven suppression in the liver [28]. Although there is much known about these individual components that needs to be considered when designing an AAV vector, the final design will most likely need to be determined empirically. It is not yet possible to know how a particular design will function by just combining the best elements together based on published reports, therefore considerable trial and error will eventually be required for deciding on the final construct. In addition, one also needs to consider the differences between in vitro and in vivo activity. Although it is possible to model rAAV expression in rodents, there is still significant concern about the translatability to humans.

AAV has evolved to enter cells through initial interactions with carbohydrates present on the surface of target cells, typically sialic acid, galactose and heparin sulfate [29, 30]. Subtle differences in sugar-binding preferences, encoded in capsid sequence differences, can influence cell-type transduction preferences of the various AAV variants [3133]. For example, AAV9 has a preference for primary cell binding through galactose as a result of unique amino acid differences in its capsid sequence [34]. It has been postulated that this preferential galactose binding could confer AAV9 with the unique ability to cross the bloodbrain barrier (BBB) and infect cells of the CNS, including primary neurons [35, 36].

In addition to the primary carbohydrate interactions, secondary receptors have been identified that also play a role in viral transduction and contribute to cell and tissue selectivity of viral variants. AAV2 uses the fibroblast/hepatocyte growth factor receptor and the integrins V5 and 51; AAV6 utilizes the epidermal growth factor receptor; and AAV5 utilizes the platelet-derived growth factor receptor. Recently, an uncharacterized type I membrane protein, AAVR (KIAA0319L), was identified as a critical receptor for AAV cell binding and internalization [37].

As a result of these subtle variations in primary and secondary receptor interactions for the various AAV variants, one can choose a variant that possesses a particular tropism and preferentially infects one cell or tissue type over others (Table). For example, AAV8 has been shown to effectively transduce and deliver genes to the liver of rodents and non-human primates, and is currently being explored in clinical trials to deliver genes for hemoglobinopathies and other diseases [38]. Likewise, AAV1 and AAV9 have been shown to be very effective at delivering genes to skeletal and cardiac muscle in various animal models [3946]. Engineered AAV1 is currently being explored as the gene transfer factor in clinical trials for heart failure, and has been approved for the treatment of lipoprotein lipase deficiency [47]. However, although different AAV vectors have been identified that preferentially transduce many different cell types, there are still cell types for which AAV has proven difficult to transduce.

Selected AAV vectors, known receptors, and known tropisms

With the strong desire to utilize AAV to deliver genes to very selective cell and tissue types, efforts to clone novel AAV variants from human and primate tissues have identified a number of unique capsid sequences that are now being studied for tropism specificities [48]. In addition, recombinant techniques involving capsid shuffling, directed evolution, and random peptide library insertions are being utilized to derive variants of known AAVs with unique attributes [4951]. In vivo-directed evolution has been successfully used to identify novel AAV variants that preferentially transduce the retinal cells of the eye, as well as other cell populations, including those in the CNS [50, 52, 53]. In addition, these techniques have been employed to identify novel AAV variants with reduced sensitivities to neutralizing antibodies (NAbs) [5457].

Alternatively, other investigators have inserted larger binding proteins into different regions of AAV capsid proteins to confer selectivity. For example, DARPins (designed ankyrin repeat proteins), portions of protein A, and cytokines, have all been engineered into the capsid of AAV for the purpose of greater cell specificity and targeting [58, 59]. Employing this concept, others have been able to selectively target AAV to tumors and CD4+ T cells, as examples of engineered tropism [60, 61].

As we continue to learn more about the biology of AAV with regard to the mechanisms involved in membrane translocation, endosomal escape, and nuclear entry, we will undoubtedly find opportunities to engineer unique properties into viral vectors through modulating one or more of these functions. For example, it has been hypothesized that surface-exposed serine and tyrosine residues could be phosphorylated upon viral cell entry, resulting in their ubiquitination and proteolytic degradation [6264]. Studies have shown that mutation of tyrosine to phenylalanine, which prevents this phosphorylation, results in dramatically improved transduction efficiencies [63]. Similar efforts have been made in attempts to limit the effects of NAbs, as discussed below.

The choice of a particular AAV to use as a gene transfer vector is heavily reliant on several critically important criteria: (1) which cell/tissue types are being targeted; (2) the safety profile associated with the delivered gene; (3) the choice of systemic versus local delivery; and (4) the use of tissue-specific or constitutively active promoters. As one gives careful consideration to these selection criteria, it is possible to narrow the choices of which AAVs (natural or engineered) to profile. Alternatively, one can begin the path of exploring fully engineered versions of AAV for truly selective cell targeting and optimized transduction. Because our understanding of AAV biology is in relative infancy, many of these efforts will remain empirical for quite some time as optimization for one activity could have a negative impact on another. Nonetheless, the future looks promising for this highly adaptable platform.

One of the appealing aspects of using rAAV as a gene transfer vector is that it is composed of biomolecules, i.e. proteins and nucleic acids. Fortunately, a full-package virus lacks engineered lipids or other chemical components that could contribute to unwanted toxicities or immunogenicities that may not be predictable or fully understood. In general, AAV has been shown to be less immunogenic than other viruses. Although not completely understood, one possible reason for this may hinge on the observation that certain AAVs do not efficiently transduce antigen-presenting cells (APCs) [65]. Additionally, unlike previous viral delivery strategies, rAAV does not contain any viral genes, therefore there will be no active viral gene expression to amplify the immune response [66]. Although AAV has been shown to be poorly immunogenic compared with other viruses (i.e. adenovirus), the capsid proteins, as well as the nucleic acid sequence delivered, can trigger the various components of our immune system. This is further complicated by the fact that most people have already been exposed to AAV and have already developed an immune response against the particular variants to which they had previously been exposed, resulting in a pre-existing adaptive response. This can include NAbs and T cells that could diminish the clinical efficacy of subsequent re-infections with AAV and/or the elimination of cells that have been transduced. It should be of no surprise that the formidable challenge is how to deliver a therapeutically efficacious dose of rAAV to a patient population that already contains a significant amount of circulating NAbs and immunological memory against the virus [67]. Whether administered locally or systemically, the virus will be seen as a foreign protein, hence the adaptive immune system will attempt to eliminate it.

The humoral response to AAV is driven by the uptake of the virus by professional APCs, and their presentation of AAV capsid peptides in the context of class II major histocompatibility proteins (MHCs) to B cells and CD4+ T cells [68, 69]. This leads to plasma cell and memory cell development that has the capacity to secrete antibodies to the AAV capsid. These antibodies can either be neutralizing, which has the potential to prevent subsequent AAV infection, or non-neutralizing. Non-NAbs are thought to opsonize the viral particles and facilitate their removal through the spleen [70].

Upon entry of the virus into target cells during the course of the natural infection process, the virus is internalized through clathrin-mediated uptake into endosomes [71]. After escape from the endosome, the virus is transported to the nucleus where the ITR-flanked transgene is uncoated from the capsid [72]. The pathway and mechanism of AAV intracellular transport and processing is not fully understood, and there are quite a few areas of debate with regard to current understanding. The most current hypothesis is that following endosomal escape, capsid breakdown and uncoating occurs after subsequent nuclear translocation. However, it is thought that cytosolic ubiquitination of the intact virus can occur during transport to the nucleus [73]. This would be a critical step in directing capsid proteins to the proteasome for proteolytic processing into peptides for class I MHC presentation. This hypothesis is supported by data in which proteasome inhibitors, or mutations in capsid residues that are sites for ubiquitination, can limit class I presentation and T-cell activation [7376]. However, apparent differences have been observed for T-cell activation to different AAV variants with significant sequence identity. At this time, it is unclear whether this is due to subtle capsid sequence differences and susceptibility to MHC I presentation or differential cellular processing that is innate to the different AAV variants, or simply due to contaminants in vector preparations [76].

In addition to an adaptive immunological reaction to the capsid of AAV, the transgene can elicit both an adaptive and an innate response. If the transgene encodes a protein that can be recognized as foreign, it too can generate a similar B- and T-cell response. For example, in replacement therapy applications in which the protein to be replaced is the consequence of a null genotype, the immune system will have never selected against precursor B and T cells to that protein [70, 77]. Likewise, if the transgene is an engineered variant, the engineered sequence can be recognized as foreign. Even the variable regions of antibodies can activate an adaptive response that can result in deletion of target cells that are expressing transgene as a result of AAV delivery. Finally, a transgene with a significant number of CpG dinucleotides can activate innate responses through toll-like receptor (TLR) molecular pattern receptors [78].

Pre-existing immunity to AAV, especially the presence of circulating NAb, can have a dramatic effect on AAV clinical efficacy. To date, this represents one of the biggest therapeutic challenges to the use of systemically delivered AAV, and is thought to be one of the factors in early clinical failures [79]. Pre-existing immunity to AAV can often be overcome by selecting a particular AAV variant that has not circulated throughout the human population, and, therefore, does not have any memory responses elicited against it, including NAbs and T cells [80]. Additionally, some of the AAV evolution technologies discussed above have been used to identify AAVs that are resistant to the effects of NAbs [50, 57]. Although not optimal, it is possible to prescreen subjects for the presence of NAbs to the particular AAV variant to be used. In addition, the impact of this immunological response can sometimes be minimized by the particular route of administration employed for the particular therapeutic strategy, as discussed in Sect. 6 [80].

Like most biotherapeutics, AAV needs to be produced in a living system (Fig.). The parallels with recombinant antibody production during the 1990s and 2000s, with regard to the upstream challenges of robust production levels, are important to understand where the industry currently is, and where we need to strive to be.

Overview of AAV production/purification. Cell platform: HEK-293T, Sf9, or other suitable cell system can be grown on a small scale on 150mm tissue culture-treated culture dish, hyperflasks, or shake flasks. Cells are then transfected with adenovirus helper virus, rep/cap, and ITR-transgene plasmids for 293T, or infected with baculovirus for Sf9. Producer lines with integrated expression of rep/cap and ITR-transgene can be infected with adenovirus and grown to scale. Scale-up: For larger-scale culture volumes, virus can be produced in roller bottles, continuous perfusion, or WAVE Bioreactor systems. Purification/polishing: Affinity or heparin chromatography are optimal for isolation of virus from culture supernatants with or without cell pellet harvesting. Benzonase/DNAse treatment of eluted virus is required for removal of extraviral DNA contamination, followed by anion-exchange chromatography to fractionate empty vs. full AAV particles. QC/release: Upper left of far right panel: image depicts a silver stain analysis of culture FT next to affinity/anion exchange purified AAV (pure). The three bands represent the viral capsid proteins VP1, VP2, and VP3. Upper right of far right panel: Dynamic light scattering analysis of purified AAV1 indicates a uniform particle distribution of approximately 2530nM. Bottom half of far right panel: Analytical ultracentrifugation can resolve the proportion of empty vs, full particles of purified material. Additional assays that should be employed are digital drop polymerase chain reaction for determining titer in GC/mL, cryo or transmission electron microscopy for visual representation of purified particles, endotoxin testing, and other assays to evaluate the presence of residual host-cell protein contamination. AAV adeno-associated virus, FT flow-through, GC genome copies, rep/cap replication/capsid, QC quality control

Current methods to produce rAAV are still expensive despite years of research (Table). The most widely used platform for producing rAAV involves transfecting HEK293 cells with either two or three plasmids; one encoding the gene of interest, one carrying the AAV rep/cap genes, and another containing helper genes provided by either adeno or herpes viruses [6]. While most robust production rates have been achieved with adherent cells in either roller bottles or cell stacks, similar rates are now achievable in suspension-adapted HEK293 cells (Table). Production rates of approximately 105 genome copies (GC)/cell are now common, resulting in 1014 GC/L [81]. While this has proven to be sufficient to support early clinical trials, and could supply marketed product for small patient population indications, the deficiencies in scalability with this platform are a significant limitation [82, 83]. As one could surmise, successfully delivering three plasmids to one cell is a relatively inefficient process. For larger-scale manufacturing efforts, transient delivery of plasmid requires excess quantities of DNA, adding to the overall cost of production and purification. Moreover, transient delivery of rep/cap genes in the presence of helper genes can also contribute to product heterogeneity, including AAV vectors lacking a transgene. These empty capsids represent a significant proportion of virus produced in transient transfection assays. Thus, it is critically important to develop robust analytical quality control (QC) methods that are able to distinguish between these viral variants in order to ensure similarities between production lots [82, 83].

Current manufacturing platforms being employed to generate rAAV for clinical use

In three other AAV manufacturing platforms, one or more genetic components for the AAV manufacturing has been integrated into the genome of mammalian or insect production cell lines. While most viral helper genes needed for AAV production cannot be stably transfected, the adenoviral E1a and E1b genes are exceptions. These genes have been used to transform HEK293 cells, however they induce expression of the AAV rep gene, which is toxic to mammalian and insect cells [84, 85]. Hence, two different approaches have been used to develop mammalian cell lines. The first uses co-infection of BHK cells with two replication-defective HSVs engineered to encode the ITR-flanked transgene and the rep/cap genes. The second is based on stable producer cell lines in HeLa cells carrying the ITR-flanked transgene and the rep/cap genes. Rep proteins are not expressed in these cells since HeLa carries no adenoviral genes. However, infection with wild-type adenovirus is required for AAV production. The inclusion of replication-competent viral agents into a production process is a concern that needs to be addressed and also requires additional steps during the downstream processing [82, 83].

More recently, the Sf9 insect cell system in combination with baculovirus infection has been utilized to produce bulk quantities of rAAV. In this system, two or three baculovirus particles may be used to infect the Sf9 cells and initiate AAV production. In one example, one virus contains the rep gene, a second contains the cap gene, and the final virus carries the ITR-flanked gene of interest. In an alternative system, the Sf9 cells can be engineered to have the ITR-flanked gene of interest integrated into their genome, upon which production is initiated with only two baculovirus preps [81, 82]. A further improvement has recently been shown whereby the rep/cap genes are stably integrated into the Sf9 cell line genome, but are under the control of a promoter/enhancer that is induced by subsequent baculovirus infection. In this system, infection can occur, with only one baculovirus containing the ITR-flanked gene of interest, simplifying the system significantly [86, 87].

Production levels of approximately 105 GC/cell and 1015 GC/L have routinely been achieved with these Sf9 systems. Because of their ease of manipulation and their ability to grow to very high cell densities, the Sf9 system is rapidly becoming the platform of choice for AAV manufacturing. Concerns regarding baculovirus instability and differences in post-translational modifications between mammalian and insect cell systems are now beginning to be understood and controlled. These concerns are offset by the fact that baculovirus cannot efficiently infect mammalian cells which makes it inherently safer then other viral-based production systems [8183, 86, 87].

Unlike antibody manufacturing that relied on a single protein A-based purification platform early in the development of the downstream process, AAV is still rapidly evolving in that area. The products of an AAV production run will contain not only cellular debris (protein/lipids/nucleic acids) but also two main populations of AAV particles: particles that contain (full capsids) or those lacking (empty capsids) the ITR-flanked transgene. Although still widely debated in the field, the presence of empty capsids represents another contaminant that must be removed or controlled. Initial attempts to separate these two populations originally relied on the cumbersome and non-scalable method of density ultracentrifugation. In addition to the scalability issue, there are also concerns about the physiochemical effects of this method on the particles. Regardless, this method is still employed by many organizations as either a primary or secondary step in AAV purification [83].

Current technologies utilizing various affinity resins and/or ion exchange chromatography are being adopted by the industry. As mentioned above, AAV uses cell membrane-associated carbohydrates as the primary cell receptor for transduction. This affinity for carbohydrates can be exploited as an initial capture step in AAV purification. Indeed, heparin columns are frequently used in many downstream processing steps for AAV [88]. However, because of the lack of specificity, alternative affinity columns based on AAV-specific binding proteins such as scFvs and antibody single domains from llamas (camelids) have started to dominate the field. Improvements in generating these AAV-specific resins confers many advantages in downstream purification. These resins have the ability to bind to more than one AAV variant, have very high binding capacities (>1014GC/mL resin), and are stable against harsh clean-in-place and regeneration methods, making them suitable for use multiple times. Some of these commercial resins are already Good Manufacturing Practice (GMP) compliant, making them ideal for downstream manufacturing at commercial scales. Polishing steps using anion exchange chromatography are now routinely included after affinity capture steps, and can efficiently separate full capsids from empty capsids [8992].

As with any new therapeutic platform, and, again, similar to antibody-based therapeutic evolution, details on product specification and regulatory requirements are still evolving. With still very limited clinical experience, the impact of empty particles, host-cell impurities, post-translational modifications from different production platforms, fidelity of the packaged transgene, capsid ratio integrity, and probably many other specifications are still not known. However, over time, and as more clinical experience is gained, the field will be able to better relate these details to product performance and safety [83].

The use of rAAV as a delivery vector for gene therapies has been rapidly gaining interest over the past 35years. As approvals begin to increase (see Sect.6), efforts to optimize and maximize clinical manufacturing technologies will see a burst of activity. This will most likely mirror what occurred with antibody therapeutics in the 1990s and 2000s, in which early technologies were quickly overcome by next-generation technologies, resulting in significant cost savings and increased clinical supplies.

AAV has been shown to be a very stable vector able to withstand wide temperature and pH changes with little to no loss in activity [93]. To date, the only limitation seems to be the concentration with which it can be formulated, currently maximized around 51013 particles per milliliter [83]. With the resurgence in clinical use, this formulation limit will most likely be overcome in the near future. However, the robust stability of these vectors provides ample opportunities to attempt different routes of administration and specialized delivery strategies (Table).

Selected examples of more than 50 clinical candidates employing rAAV

Other than the European Medicines Agency (EMA)-approved AAV-based product alipogene tiparvovec (Glybera), the most advanced current clinical trial using AAV is sponsored by Spark Therapeutics and utilizes local injection of AAV2 into the eye for inherited retinal diseases (voretigene neparvovec-RPE65) (Table) [94]. Phase III studies have just been completed on this candidate and a Biologics License Application (BLA) submission is expected this year. This type of local delivery has proven to be safe and efficacious, but requires specialized surgical techniques and/or devices to deliver the vector [94, 95]. Similar strategies are being conducted by Applied Genetic Technologies Corporation (AGTC), targeting X-linked retinoschisis and achromatopsia, X-linked retinitis pigmentosa, and age-related macular degeneration. These programs are at various stages of development, with the most advanced for X-linked retinoschisis and achromatopsia in phase I safety studies (http://www.AGTC.com) (Table).

Several clinical trials are being run in which systemic administration is being used to target the liver, a tissue that is readily accessible through this route of administration and a tissue type that is readily transduced by many well-understood AAV variants [96]. These trials are mostly for monogenic, inherited diseases, in which the goal is gene replacement for defective genes, including those mutated in hemophilia A and B. Currently, these trials are in phase I/II, and are sponsored by academic groups, as well as biopharmaceutical companies such as Spark Therapeutics (SPK-9001, SPK-8011), Sangamo Therapeutics (SB-525), UniQure (AMT-060), Dimension Therapeutics (DTX101, DTX201), and Biomarin (BMN 270) (Table) [97]. Unlike local administration to the eye, which is considered an immune-privileged site that might not be affected by the existence of NAbs, systemic administration will require patient stratification for patient NAb levels. In addition, the possibility for re-administration becomes very difficult, should the need arise [80]. Although rare, there have been reports of rAAV vector integration into animal model genomes with subsequent genotoxicities [98, 99]. In addition, AAV genome sequences have been found in human hepatocellular carcinoma samples near known cancer driver genes, although at a low frequency [100]. There is an ongoing debate on these findings regarding cause and effect, and mouse/human translation. Regardless, hepatocellular, as well as other tissue genotoxicity, will need to be monitored in the course of AAV clinical development.

Another common delivery strategy is direct intramuscular injections. The only approved AAV gene therapy in Europe (Glybera) is an AAV1 encoding the gene for lipoprotein lipase deficiency [47, 101]. Skeletal muscle has been shown to be a target tissue type that is efficiently transduced by many AAV variants [39]. Once transduced, the muscle cells serve as a production site for protein products that can act locally or systemically, as is the case with Glybera. As a result of the low cellular turnover rate of the muscle cells, the transduced AAV gene product will be maintained in these cells as an episome for years, as has been shown in many studies in non-human primates [39]. Consequently, a single-dose regimen of an intramuscularly-delivered product may never need to be readministered unless there is significant damage or immune clearance of the transduced cells. This strategy is also being employed by Adverum and AGTC for 1-antitrypsin deficiency, as well as for certain muscular dystrophies (Table) [97].

Direct CNS administration is being utilized for Parkinsons disease, as well as various inherited diseases such as Batten disease, Canavan disease, and mucopolysaccharidosis (MPS) IIA and IIB, as well as MPS IIIa and MPS IIIb (Sanfilippo syndromes type A and type B, respectively). Phase I/II studies for these diseases using a variety of AAV variants, including AAV2, AAVrh10, and AAV9, are currently ongoing by various academic groups and biopharmaceutical companies, such as Abeona Therapeutics (ABO-101, ABO-102, ABO-201, ABO-202) [97, 102, 103]. Delivery strategies range from direct intraparenchymal administration into particular areas of the brain, intracerebroventricular, and cisternal and lumbar intrathecal routes [102]. The decision on the best route of administration is intimately related to the disease and affected areas. For example, for Parkinsons disease, according to our current understanding of disease pathogenesis and therapeutic strategies, direct injection into the putamen, substantia nigra or striatum is thought to be required. Similarly, for diseases that affect larger areas of the brain, such as Canavan disease or MPS, direct injection into the cerebellum is thought to be most beneficial [102, 103].

Alternatively, administration directly into the cerebrospinal fluid through an intrathecal route can result in wide CNS biodistribution, which is thought to be necessary for diseases such as spinal muscular atrophy (SMA) and Alzheimers disease [102106]. An alternative to cerebral spinal fluid (CSF)-based routes is the use of systemic administration of AAV variants that have been shown to cross the BBB. AAV9 has been shown to transcytosis across the BBB and transduce large sections of the CNS [36, 104, 107, 108]. This approach is currently being explored in the clinic for the treatment of SMA by AveXis (AVXS-101).

Neurodegenerative diseases represent a particular devastating health problem for which there is significant unmet medical need. These diseases of the CNS have proven to be very difficult to treat as a result of our poor understanding of their etiology and difficulty getting efficacious agents across the BBB. With regard to Alzheimers disease, although there is still some disagreement in the field, idiopathic amyloid plaque formation or generation of neurofibrillary tau tangles (NFTs), both of which are thought to be neurotoxic, are still the prevailing hypotheses behind the mechanism of many of these neuropathologies. Attempts to clear these plaques with plaque-specific antibodies have shown signs of limiting this process in animals and early-stage clinical trials [109, 110]; However, larger studies have all shown to be inconclusive at best, or failures at worst. It is unclear if these failures were because the plaque hypothesis is wrong, or if there was inefficient CNS exposure to the antibody therapeutic [110, 111]. Alternative strategies taking advantage of the safety and persistence of AAV would utilize either local administration of antibody-encoding AAVs directly to the CNS, or systemic delivery of AAVs that can cross the BBB, resulting in significantly higher CNS exposure levels of the antibody [112].

Local delivery of AAV to cardiac muscle for heart failure has been attempted in various clinical trials. In one case, Celladon failed in their attempt to deliver SERCA2A directly to the heart, and, in a second case, there is an ongoing program sponsored by UniQure to deliver S100A directly to the heart that is currently still in preclinical development [46, 113115]. Although it is not thoroughly clear why Celladon failed in the clinic, and why one would expect UniQure/BMS to succeed, there are significant differences in the delivery methods used by the two programs and the target gene delivered. Celladon used intracoronary infusion to deliver their AAV1 SERCA2A gene product, whereas UniQure is using retroinfusion and left anterior descending (LAD) coronary occlusion [41, 115]. This procedure is thought to better localize and restrict the delivered AAV9 S100A gene product to better target the heart tissue of interest. The reality of this suspected benefit will be realized in the clinic in the coming years.

Aerosolized AAV for inhaled pulmonary delivery was utilized in some of the earliest trials for cystic fibrosis (CF). Although none of these trials resulted in significant benefit or showed much of a pharmacodynamic response, they did help to show the safety of AAV when administered via this route [116118]. More importantly, the pathophysiology of CF, molecular biology of the CF transmembrane conductance regulator (CFTR) gene, and the target cell population for this type of indication exposed some key considerations when using AAV [117]. Congestion of the airways in these patients can limit AAV biodistribution after delivery, thus attenuating robust transduction [118]. In addition, the CFTR gene is over 4kb in size, putting it at the upper limit of the packaging capacity of AAV after also considering a required promoter and terminator. Finally, CFTR is expressed by the submucosal glands, which may be difficult to target efficiently [116, 117]. Nonetheless, these early efforts proved that AAV can safely deliver genes to the lung, which might be an ideal strategy for other diseases, such as influenza and other infectious diseases of the lung [119].

The field is just beginning to explore localized delivery of AAV for gene therapy applications. The stability of the virus and broad tropism for many different cell and tissue types make them ideal for most applications. There appears to be at least one AAV variant option for every tissue type of interest, with engineering and novel AAV discovery efforts sure to identify and create AAV variants with very specialized functions on demand. These efforts will undoubtedly result in new therapeutic strategies for many new indications.

The transfer of genes and other nucleic acids into cells has been a research tool in the laboratory for more than four decades. However, it was our growing understanding of the genetic components underlying certain diseases that has driven the search for true gene therapies. Progressively, research in other areas have identified other potential opportunities in which gene delivery could be applied therapeutically. In addition, limitations with current small molecule and protein therapeutic platforms have also driven the search for alternative therapeutic platforms that accommodate those limitations [120, 121]. Gene therapies accommodate all of those limitations, especially around target accessibility. As a result, the search for safe and effective gene delivery technologies has been a major focus in pharmaceutical research and development, and will hopefully represent a paradigm shift in how we approach disease-state intervention.

AAV was discovered over 50years ago and has since become one of the leading gene delivery vectors in clinical development. As a result of its unique biology, simple structure, and no known disease associations, AAV could become the vector of choice for most gene therapy applications. Gene therapy using rAAV has been demonstrated to be safe and well-tolerated in virtually every clinical setting in which it has been used. These studies, along with basic research on its biology, have revealed many facets of this vector that can be applied to future efforts.

Among the critical parameters to be considered are vector design, capsid selection, desired target cell and tissue type, and route of administration. The transgene to be delivered optimized for expression, the right AAV variant with an appropriate capsid for target cell transduction and immunoreactivity profile, and the appropriate delivery approach to maximize target tissue exposure while limiting off-tissue exposure are key focal points for AAV-based therapies.

All of these variables will be dictated by the overall therapeutic strategy which will be influenced by our understanding of the pathobiology of the disease to be treated. Will the transgene have the desired effect? Is the target cell driving the disease state? Is the turnover rate of the target cell high, requiring repeat dosing? This cannot be emphasized enough; without a strong understanding of the mechanisms driving the disease state, it will not be possible to design, discover, and develop the right gene therapeutic. Better designed trials, optimized vector construction, and novel AAV variants will certainly result in future regulatory approvals and improvements on patient outcomes and health.

Michael F. Naso, Brian Tomkowicz, and William L. Perry III are employees of Janssen Research and Development. William R. Strohl has no conflicts of interest to declare.

No funding was received for the preparation of this review.

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Adeno-Associated Virus (AAV) as a Vector for Gene Therapy

FDA approves novel gene therapy to treat patients with a rare form of …

For Immediate Release: December 18, 2017

Espaol

The U.S. Food and Drug Administration today approved Luxturna (voretigene neparvovec-rzyl), a new gene therapy, to treat children and adult patients with an inherited form of vision loss that may result in blindness. Luxturna is the first directly administered gene therapy approved in the U.S. that targets a disease caused by mutations in a specific gene.

Todays approval marks another first in the field of gene therapy both in how the therapy works and in expanding the use of gene therapy beyond the treatment of cancer to the treatment of vision loss and this milestone reinforces the potential of this breakthrough approach in treating a wide-range of challenging diseases. The culmination of decades of research has resulted in three gene therapy approvals this year for patients with serious and rare diseases. I believe gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable illnesses, said FDA Commissioner Scott Gottlieb, M.D. Were at a turning point when it comes to this novel form of therapy and at the FDA, were focused on establishing the right policy framework to capitalize on this scientific opening. Next year, well begin issuing a suite of disease-specific guidance documents on the development of specific gene therapy products to lay out modern and more efficient parameters including new clinical measures for the evaluation and review of gene therapy for different high-priority diseases where the platform is being targeted.Luxturna is approved for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy that leads to vision loss and may cause complete blindness in certain patients.

Hereditary retinal dystrophies are a broad group of genetic retinal disorders that are associated with progressive visual dysfunction and are caused by mutations in any one of more than 220 different genes. Biallelic RPE65 mutation-associated retinal dystrophy affects approximately 1,000 to 2,000 patients in the U.S. Biallelic mutation carriers have a mutation (not necessarily the same mutation) in both copies of a particular gene (a paternal and a maternal mutation). The RPE65 gene provides instructions for making an enzyme (a protein that facilitates chemical reactions) that is essential for normal vision. Mutations in the RPE65 gene lead to reduced or absent levels of RPE65 activity, blocking the visual cycle and resulting in impaired vision. Individuals with biallelic RPE65 mutation-associated retinal dystrophy experience progressive deterioration of vision over time. This loss of vision, often during childhood or adolescence, ultimately progresses to complete blindness.

Luxturna works by delivering a normal copy of the RPE65 gene directly to retinal cells. These retinal cells then produce the normal protein that converts light to an electrical signal in the retina to restore patients vision loss. Luxturna uses a naturally occurring adeno-associated virus, which has been modified using recombinant DNA techniques, as a vehicle to deliver the normal human RPE65 gene to the retinal cells to restore vision.

The approval of Luxturna further opens the door to the potential of gene therapies, said Peter Marks, M.D., Ph.D., director of the FDAs Center for Biologics Evaluation and Research (CBER). Patients with biallelic RPE65 mutation-associated retinal dystrophy now have a chance for improved vision, where little hope previously existed.

Luxturna should be given only to patients who have viable retinal cells as determined by the treating physician(s). Treatment with Luxturna must be done separately in each eye on separate days, with at least six days between surgical procedures. It is administered via subretinal injection by a surgeon experienced in performing intraocular surgery. Patients should be treated with a short course of oral prednisone to limit the potential immune reaction to Luxturna.

The safety and efficacy of Luxturna were established in a clinical development program with a total of 41 patients between the ages of 4 and 44 years. All participants had confirmed biallelic RPE65 mutations. The primary evidence of efficacy of Luxturna was based on a Phase 3 study with 31 participants by measuring the change from baseline to one year in a subjects ability to navigate an obstacle course at various light levels. The group of patients that received Luxturna demonstrated significant improvements in their ability to complete the obstacle course at low light levels as compared to the control group.

The most common adverse reactions from treatment with Luxturna included eye redness (conjunctival hyperemia), cataract, increased intraocular pressure and retinal tear.

The FDA granted this application Priority Review and Breakthrough Therapy designations. Luxturna also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a Rare Pediatric Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the 13th rare pediatric disease priority review voucher issued by the FDA since the program began.

To further evaluate the long-term safety, the manufacturer plans to conduct a post-marketing observational study involving patients treated with Luxturna.

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

Luxturna is the first gene therapy approved in the U.S. to target a disease caused by mutations in a specific gene

Andrea Fischer301-796-0393

888-INFO-FDAOCOD@fda.hhs.gov

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FDA approves novel gene therapy to treat patients with a rare form of ...

Gene therapy: Where the action is for retinal diseases – Modern Retina

Foundation Fighting Blindness is a driving force in advancing retinal gene therapies into clinical trials.

Growth in the clinical and commercial development of gene therapies for retinal degenerative diseases has been explosive over the past decade. The rapid expansion of the field has been led by dramatic vision restoration for virtually blind patients made possible by voretigene neparvovec-rzyl(Luxturna; Spark Therapeutics), which the FDA approved in December 2017. It is the first gene therapy for the eye or any inherited retinal disease to cross the regulatory finish line in the United States. Developed by gene therapy pioneer Jean Bennett, MD, PHD, for children and adults with Leber congenital amaurosis (LCA) or retinitis pigmentosa (RP) caused by biallelic RPE65 mutations, the therapy provided immediate and impressive vision improvements in a phase 1/2 clinical trial at Childrens Hospital of Philadelphia. Those initial results, reported in 2008, sent a strong signal to investigators and biotechnology companies that gene therapy could be a powerful modality for treating retinal diseases.

Now, dozens of companies are in the retinal gene therapy development space and more than 20 clinical trials for genetic therapies are underway for patients with a broad range of retinal degenerative diseases. These include RP, LCA, choroideremia, achromatopsia, and the dry and wet forms of age-related macular degeneration (AMD).

The Foundation Fighting Blindness, the worlds leading private funder of retinal degenerative research, has played a pivotal role in advancing retinal gene therapies into clinical development. As an early funder of the modality for myriad retinal diseases, the foundation began investing in RPE65 gene therapy research back in the mid-1990s and ultimately invested $10 million in the research that eventually led to voretigene neparvovec.

We were very early adopters, recognizing that the retina was an ideal gene therapy target. Its a small, accessible piece of tissue, and many conditions that affect the retina are monogenic. We knew that if we could directly address the patients mutated gene by augmenting or modifying its activity, we had an excellent opportunity to save and restore vision, said Benjamin Yerxa, PhD, chief executive officer at the foundation. Furthermore, we see gene therapys potential for gene-agnostic applications such as neuroprotection and optogenetics to help a broad range of patients, regardless of the mutated gene causing their vision loss.

The foundation currently funds a broad range of gene therapies and other treatment modalities at both early and late stages of development. Its RD (Retinal Degeneration) Fund, a venture philanthropy fund with nearly $120 million in commitments, was launched in 2018 to help investigators and start-up companies move their emerging therapies into and through early-stage clinical trials. The funds goal is to attract additional investments from pharmaceutical and biotechnology companies to fund the more expensive, late-stage trial phases. Furthermore, all returns on the funds investments are put back into the foundation to support additional research and investments.

The ultimate goal of the RD Fund is to get more treatments across the finish line and out to patients. We cant afford to fund late-stage clinical research, which often costs a hundredmillion dollars or more, but we can afford the earlier-stage research to attract those major investments from biotechs and big pharma, said Yerxa.

In fall 2021, the RD Fund took the bold step of launching its own company, Opus Genetics, to develop gene therapies for orphan retinal diseases, those rare conditions that werent being addressed by other companies. Opus $19 million in seed financing included investments from the Manning Family Foundation and Bios Partners. Its first 3 targets are for LCA caused by mutations in LCA5, RDH12, and NMNAT1. The LCA5 and RDH12 therapies were developed preclinically by Opus cofounder Bennett and licensed from the University of Pennsylvania. The NMNAT1 treatment was developed in the laboratory by cofounder Eric A. Pierce, MD, PhD, and licensed from Harvard Medical Schools Massachusetts Eye and Ear. Opus plans to launch a clinical trial for LCA5 by the end of 2022. In April 2022, the company signed a collaboration agreement with Resilience to provide manufacturing services for its gene therapy pipeline.

In October 2020, the RD Fund realized its first financial win when Novartis acquired Vedere Bio for around $280 million. In 2019, the fund had helped launch Vedere Bio to advance an optogenetic therapy developed by its scientific cofounders John G. Flannery, PhD, and Ehud Isacoff, PhD, from the University of California, Berkeley. The investigators approacha gene-agnostic gene therapyprovides potential vision restoration for patients who have lost all their photoreceptors to a condition such as RP by delivering a gene that expresses a light-sensing green cone opsin in surviving ganglion cells. In essence, the treatment enables ganglion cells to work like a back-up system for lost photoreceptors. The approach holds promise for restoring vision for patients who are completely or nearly blind, regardless of the mutation causing their disease. A new incarnation of the company, Vedere Bio II, was subsequently launched after the Novartis acquisition to continue development of other retinal gene therapies.

Also in 2020, the RD Fund invested in the gene therapy start-up Atsena Therapeutics, which reported early, encouraging vision improvements for 3 patients in a phase 1/2 clinical trial for its LCA (GUCY2D mutations) gene therapy. Cofounded by Shannon E. Boye, PhD, and Sanford L. Boye, MS, both of the University of Florida in Gainesville, Atsena also has preclinical gene therapy programs for X-linked retinoschisis and Usher syndrome type 1B.

SparingVision, another RD Fund investment, is planning to launch a clinical trial in 2022 for its gene-agnostic, cone-preserving therapy for patients with RP, Usher syndrome, and related conditions. Nearly 2 decades ago, Jos-Alain Sahel, MD, and Thierry Lveillard, PhD, investigators from the Institut de la Vision in Paris, France, identified a protein secreted by rod photoreceptors that is critical to the survival of cones. Aptly named rod-derived cone-viability factor, it is the protein expressed by SparingVisions cone-preserving gene therapy. The company is also developing a gene therapy that restores light sensitivity to cones that have lost their ability to process light due to advanced forms of RP, Usher syndrome, and related diseases.

The RD Funds other gene-related therapy investments include SalioGen Therapeutics, whose Saliogase technology seamlessly inserts new DNA of any size (eg, the Stargardt disease gene ABCA4) into precise, defined genomic locations. The fund also invests in ProQR Therapeutics, which has an RNA therapy in a phase 2/3 clinical trial for individuals with Usher syndrome 2A and nonsyndromic RP caused by mutations in exon 13 of the USH2A gene.

We are off to a great start with our investments and working to continue to expand our portfolio with the strategy of investing in strong science being developed by well-managed companies, said Yerxa. I think our coinvestors recognize and appreciate our commitment to making every shot on goal really count.

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Gene therapy: Where the action is for retinal diseases - Modern Retina

Adverum cuts jobs, restructures to give eye gene therapy another shot – BioPharma Dive

Dive Brief:

Despite significant setbacks that have left the fate of its eye gene therapy in doubt and shares trading near all-time lows, Adverum hasnt given up.

The company is one of a few gene therapy makers aiming to develop a one-time treatment for diabetic macular edema and age-related macular degeneration, two common forms of vision loss that are treated with chronic injections of biologic medicines. But those drugs, like Eylea and Lucentis, are highly effective and considered safe, making the bar much higher for a gene therapy whose main goal is to improve convenience.

Adverums program was also beset by side effects the company once described as not seen before in ocular gene therapy, a combination of inflammation, vision loss and decrease in eye pressure observed in five trial participants.

Adverum stopped that trial, in diabetic macular edema, in 2021. At the time, some analysts suggested the company should attempt a reverse merger, a way for struggling biotechs to bring in new assets by combining with a privately held company seeking fast access to the public markets.

The company instead vowed to press on. Executives suggested testing a lower dose than previously planned with a different regimen of protective drugs could lead to better results in AMD. In 2021, the company noted that no cases of severe inflammation were observed in DME patients treated with a lower dose or in participants with AMD in another trial.

Adverum has since gained clearance from U.S. regulators for its new plan, a Phase 2 trial in AMD thatll test both the lowest dose evaluated in previous studies as well as one more than three-times lower. With shares trading at just over $1 apiece and equity harder to raise during the sectors downturn, Adverum has turned to cost-cutting to save money and fund the work. The savings could enable the company to get to one-year results from that trial, in 2023, without needing to raise more cash, wrote RBC analyst Luca Issi.

Yet Adverums odds remain long. A rival gene therapy from Regenxbio is already in Phase 3 testing in AMD, and pending positive results, could lead to an approval filing in 2024. The company remains a show-me story given its history, Issi wrote. Additionally, Adverums decision to turn to layoffs, rather than a partnership, may also signal limited strategic interest in the platform, he added.

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Adverum cuts jobs, restructures to give eye gene therapy another shot - BioPharma Dive