Category Archives: Gene therapy

TOKYO, July 1, 2020 /PRNewswire/ --Hitachi, Ltd.(TSE: 6501, "Hitachi") and ThinkCyte, Inc. ("ThinkCyte") today announced that they have entered into a collaboration focused on developing an artificial intelligence (AI)-driven cell analysis and sorting system. Hitachi provides a broad range of solutions such as automated cell culture technologies to pharmaceutical companies in the value chain*1 of the regenerative medicine and cell therapy industry. Through the addition of this cell analysis and sorting system to the value chain, Hitachi continues contributing to cost reductions in the manufacturing of regenerative medicine and cell therapy products.Further, Hitachi and ThinkCyte are promoting collaboration with pharmaceutical companies and research institutes working in the field of regenerative medicine and cell therapy to expedite the development of the system toward commercialization.

The practical applications of regenerative medicine and cell therapy using cells for treatment have been expanding rapidly with the first regulatory approval of CAR-T*2 therapy for leukemia in 2017 in the United States and 2019 in Japan. The global market for regenerative medicine and cell therapy is expected to grow from US$ 5.9 billion (JPY 630 billion) in 2020 to US$ 35.4 billion (JPY 3.8 trillion) in 2025*3. In order to scale up treatment using regenerative medicine and cell therapy products, it is critical to ensure consistent selection and stable supply of high quality cells in large quantities and at a low costs.

Hitachi has been providing large-scale automated induced pluripotent stem (iPS) cell culture equipment, cell processing facilities (CPFs), manufacturing execution systems(MES), and biosafety cabinets among other products to pharmaceutical companies and research institutes, and has developed a value chain to meet a variety of customer needs in the regenerative medicine and cell therapy industry. Hitachi has also been carrying out collaborative research projects with universities, research institutes, and other companies to develop core technologies for pharmaceutical manufacturing instruments and in vitro diagnostic medical devices, prototyping for mass production, and working on manufacturing cost reduction and the development of stable and reliable instruments.

ThinkCyte has been performing research and development focused on high-throughput single cell analysis and sorting technology to precisely analyze and isolate target cells. While such single cell analysis and sorting technologies are vital to life science and medical research, it has been thought impossible to achieve high-throughput cell sorting based on high-content image information of every single cell. ThinkCyte has developed the world's first Ghost Cytometrytechnology to achieve high-throughput and high-content single cell sorting*4and has been conducting collaborative research projects with multiple pharmaceutical companies and research institutes to utilize this technology in life science and medical fields.

Hitachi and ThinkCyte have initiated a joint development of the AI-driven cell analysis and sorting system based on their respective technologies, expertise, and know-how. By combining ThinkCyte's high-throughput and high-content label-free single cell sorting technology and Hitachi's know-how and capability to producing stably operative instruments on a large scale, the two companies will together develop a novel reliable system to enable high-speed label-free cell isolation with high accuracy, which has been difficult to achieve with the existing cell sorting techniques, and to realize stable, low-cost and large-scale production of cells for regenerative medicine and cell therapy.

Hitachi and ThinkCyte will further advance partnerships with pharmaceutical companies and research institutes that have been developing and manufacturing regenerative medicines and cell therapy products in Japan and other countries where demand is expected to be significant, such as North America, in order to make this technology a platform for the production of regenerative medicines and cell therapy products. At the same time, taking advantage of the high-speed digital processing technologies cultivated through the development of information and communication technology by the Hitachi group, Hitachi will integrate this safe and highly reliable instrument in its value chain for regenerative medicine and contribute to the growth of the regenerative medicine and cell therapy industry.

Note:

*1. Cell manufacturing processes, including cultivation, selection, modification, preservation, product quality control, etc.

*2. Chimeric Antigen Receptor T cells that have been genetically engineered to produce an artificial T-cell receptor for use in immunotherapy.

*3. Division of Regenerative Medicine, Japan Agency for Medical Research and Development, The final report for market research on regenerative medicine and gene therapy (2020).

*4. S, Ota et al., Ghost Cytometry, Science, 360, 1246-1251 (2018).

About the AI-driven cell analysis and cell sorting technologyThinkCyte has developed high-throughput image-based cell sorting technology based on the Ghost Cytometry technology by integrating the principles of advanced imaging technology, machine learning, and microfluidics. By applying structured illumination to cell imaging, structural information of a single cell can be converted to one-dimensional waveforms for high-throughput data analysis. Based on the judgment of a machine-learning (AI) model developed using the waveform data, target cells are isolated in a microfluidic device with high throughput and with minimal damage to the cells.

This data analysis approach eliminates time-consuming image reconstruction processes and allows high-throughput image-based single cell sorting, enabling the discrimination of cells that were previously considered difficult to distinguish by the human eye. Conventional cell sorting methods rely on the use of labels such as cell surface markers for cell sorting; in contrast, ThinkCyte's technology can sort cells without such labels by employing this unique approach. In addition to the field of regenerative medicine and cell therapy, this technology can also revolutionize drug discovery and in vitrodiagnostics fields.

About Hitachi, Ltd.Hitachi, Ltd. (TSE: 6501), headquartered in Tokyo, Japan, is focused on its Social Innovation Business that combines information technology (IT), operational technology (OT) and products. The company's consolidated revenues for fiscal year 2019 (ended March 31, 2020) totaled 8,767.2 billion yen ($80.4 billion), and it employed approximately 301,000 people worldwide. Hitachi drives digital innovation across five sectors - Mobility, Smart Life, Industry, Energy and IT - through Lumada, Hitachi's advanced digital solutions, services, and technologies for turning data into insights to drive digital innovation. Its purpose is to deliver solutions that increase social, environmental and economic value for its customers. For more information on Hitachi, please visit the company's website at https://www.hitachi.com.

About ThinkCyte, Inc.ThinkCyte, headquartered in Tokyo, Japan, is a biotechnology company, which developsinnovative life science research, diagnostics,and treatmentsusingintegrated multidisciplinary technologies, founded in 2016. The company focuses on the research and development of drug discovery, cell therapy, and diagnostic platforms using its proprietary image-based high-throughput cell sorting technology In June 2019, the company was selected for J-Startup by the Ministry of Economy, Trade and Industry of Japan. For more information on ThinkCyte, please visit the company's website at https://thinkcyte.com.

ContactsHitachi, Ltd.Analytical Systems Division, Healthcare Division, Smart Life Business Management Divisionhttps://www8.hitachi.co.jp/inquiry/healthcare/en/general/form.jsp

ThinkCyte, Inc.https://thinkcyte.com/contact

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Hitachi and ThinkCyte announce collaboration to develop an AI-driven cell analysis and sorting system - BioSpace

In its rather short life, the gene therapy field has been on a rollercoaster of experiences. While the initial hype was dampened by failures in clinical trials, the field is now experiencing a strong comeback. What was once seen as a hope, is now becoming a reality. But producing viral vectors, the essential delivery vehicles of gene therapies, remains challenging. CEVEC Pharmaceuticals has found a solution and developed a platform that can produce adeno-associated viral vectors (AAVs) as easily as if they were monoclonal antibodies.

As the gene therapy field grows, drug developers are confronted with the fact that most gene therapy products cant be produced at the scale needed to meet growing demands. The reason: lack of adequate viral vector production technologies. What gene therapy developers desperately need is a production platform that can produce viral vectors simply, with no variations, avoiding cumbersome processes, and at reasonable costs.

I have spoken to Nicole Faust, CEO at CEVEC Pharmaceuticals about the challenges in viral vector production, how these are addressed with the companys brand new production platform for AAVs, ELEVECTA, and what it has in common with standardized production platforms that already exist for monoclonal antibodies.

The great thing about gene therapy is that you can, in many cases, tackle the underlying cause of the disease. A lot of diseases today are just treated symptomatically, but with gene therapy, if the underlying cause is a gene defect, you can bring an intact copy of the gene into the patient or even repair the gene using genome editing tools like CRISPR-Cas.

To be able to do so, you need vehicles to deliver the gene. In most cases, although there are a number of non-viral approaches out there, the researchers use viral vectors. This makes a lot of sense because thats what a virus does it delivers genes to cells. Were exploiting that feature of the virus, replacing the viral genes with the therapeutic gene, and using that viral vector to deliver the therapeutic gene to the target cells.

At the moment, there are three different viral vector types mainly used for gene-therapy approaches. One of them is the lentiviral vector, which has the advantage of integrating the gene into the cells, so it will stay there permanently. But lentiviral vectors also bear some risks because they can integrate into an unwanted position in the genome.

At the moment, lentiviral vectors are mainly used for ex-vivo therapies, in particular, because they are very good for transducing hematopoietic cells. Novartis Kymriah, for example, is a CAR-T therapy that uses a lentiviral vector to deliver the Chimeric Antigen Receptor (CAR) to T-cells outside of the patient. Then the modified cells are given back to the patient.

Second, there are adenoviral vectors, which were basically used when gene therapy started more than 20 years ago. They are still being used, but mainly for vaccination approaches. For example, there are some SARS-CoV-2 vaccines being developed at the moment with adenoviral vectors.

When we talk about in vivo gene therapies actually delivering the therapeutic gene to the target cells inside the patient then nearly always AAVs are used. The reason is that AAVs are non-pathogenic and the virus always needs the presence of a helper virus to replicate, and this makes it a lot safer than other viral vectors.

AAV is also a very interesting virus because it comes in a lot of different serotypes different species of AAV. These serotypes correspond to distinctive structures on the surface of the virus, and that means that different tissues can be targeted. If you want to target neural tissue, for example, youll use a different AAV serotype than if you target the liver or muscles.

Another advantage of the AAV is that the particles themselves are very robust and very stable. They are easy to purify and once youve purified them, you can store them for a very long time without losing activity. All that makes them a nearly perfect tool for gene therapy.

Upscaling is one of the biggest challenges in AAV production. The reason is that most of these therapies come out of universities, which means the first viral vectors were produced in a research lab by a method that would yield just enough vector material to do lab experiments. These methods work very well at this level, but they are not really scalable.

Also, in many cases, the viral vector production is based on adherently growing cells, so the cells need a substrate to adhere to in order to survive and divide. That means you cant just use a huge 2000 L bioreactor, but you really have to provide the cells with a substrate and this is difficult at a large scale.Also, adherent cells are not a good solution for scalability because, very often, they still require animal-derived serum to grow, which presents a potential safety issue.

So instead, more and more suspension cell lines are being developed. But these cells still share one problem with adherent cells: Production of AAVs relies on a method called transient transfection.

What does that mean? To make an AAV, you have to bring into the cell different genetic elements. You need one plasmid that carries the rep and cap genes for the AAV life cycle and for producing the capsid; you need a second plasmid with the adenoviral helper gene; and a third plasmid with the therapeutic gene of interest, which is flanked by the recognition sequences that will allow the gene of interest to be packaged into the AAV vector.

So, you can imagine, transient transfection is convenient if you do it at a small scale in a lab,but its a challenge if you need to do it at several hundred liters. Its not only a challenge with respect to the complexity of the process, but it also means you have to provide a lot of plasmid material.

The common understanding is that plasmids used for transient transfection in vector manufacturing for use in humans need to fulfill good manufacturing practice (GMP) requirements, which makes them very expensive. The plasmid costs can make up one-third of the production cost of a batch. Thats obviously a huge cost factor. You also need a transfection reagent. Often, there are sourcing issues and it can sometimes take up to half a year until you finally get the plasmid you need for your GMP production round.

At the moment, were still talking about ultra-rare diseases where batch sizes arent large. But a lot of common diseases, like Alzheimers and Parkinsons, are currently in gene therapy trials. Once these trials are successful and they go into clinical phase III or even enter the market, then upscaling becomes a huge challenge. How will we produce sufficient amounts of the vectors in sufficient quantity and quality?

With ELEVECTA, our new scalable, stable producer cell line technology for AAV gene therapy vectors, we wanted to address all the challenges I just mentioned. First of all, we have eliminated the lengthy and complex transfection step. Our platform does not require any transfection for the actual production of the AAV vector, which also means it doesnt require any plasmid or transfection reagent. So, we dont need any of the expensive raw materials.

ELEVECTA is truly scalable because its basically made AAV production very similar to the well-established recombinant protein production methods. Using our platform, AAV production is very much like making a monoclonal antibody. With this, were addressing the major challenges that people are seeing for AAV production.

Weve been thinking about how people have mastered the production of other biotherapeutics like monoclonal antibodies and why their production is scalable, and the answer is relatively simple: because they are using true, stable producer cell lines. That means all the genetic information thats required to make the product is stably integrated into a producer cell.

Of course, we have to do cell line development in the beginning, but that only needs to be done once. Then, the producer cell line can be used for the production of the gene therapy vector for an unlimited period, as all the components are integrated into the cells genome.

I like making the comparison to monoclonal antibodies because making a monoclonal antibody used to be difficult, but its now become a common technology that can be outsourced to numerous service providers. We wanted to accomplish the same for AAVs. With our ELEVECTA producer cells, were now able to do so.

Developing the ELEVECTA technology was not trivial and we had to apply some tricks from the molecular biology toolbox, but we have been successful in the end. And we have very convincing data from true producer cells where we generated AAV vectors in large bioreactors with consistent productivity and quality.

One of the important quality measures is the full-versus-empty ratio because you always also generate empty particles that will not carry your gene of interest. Thats just inherent to AAVs. With our ELEVECTAplatform, we see a high ratio of full particles, which is what you are looking for, and its also consistent over different batches, making the process more robust and subsequent purification easier.

We want to make ELEVECTAwidely available and we want to see it in use for most of the future AAV gene therapy products. We will help interested parties make their specific producer cell lines with their specific gene of interest and their specific serotype

We are also supporting Pharma companies with a whole portfolio of products by offering a partner package and enabling them to do everything themselves, including cell line development.

But for most clients, we offer product-based projects. This means we generate stable producer cell lines as a service and then transfer those cells and the corresponding manufacturing processes to our clients who then use them under a technology license.

I believe that gene therapy has overcome the initial hurdles now and we will see many more products on the market in the future. But this also means that the therapy costs have to go down. At the moment, were talking about one million or two million for a treatment. Thats a big obstacle to making gene therapies commonly available. One important factor in addressing this issue is lowering production costs.

The standard size of a transient production run is about 200 L. With ELEVECTA, its not a problem to scale up to 2000 L and beyond. So, in addition to reducing the material costs, our clients can benefit significantly from the economy of scale while using standardized processes, equipment, and facilities as known from antibody production.

Are you struggling to find an upscaling solution for your gene therapy? Get in touch with the experts at CEVEC and visit their website for more information!

Images via Shutterstock.com and CEVEC

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How to Solve the Production Challenges of AAVs for Gene... - Labiotech.eu

PHILADELPHIA, June 01, 2020 (GLOBE NEWSWIRE) -- Spark Therapeutics, a fully integrated, commercial gene therapy company dedicated to challenging the inevitability of genetic disease, today announced the publication of new research in the journal Nature Medicine demonstrating that treatment with immunoglobulin G-degrading (IgG) enzyme of Streptococcus pyogenes (IdeS) resulted in rapid and transient reduction of neutralizing anti-adeno-associated virus (AAV) antibodies and restored gene therapy efficacy in controlled laboratory tests of animal models.

One of the main challenges associated with AAV-mediated gene therapy is neutralizing antibodies that can impact the ability to administer gene therapy, saidFederico Mingozzi, Ph.D., chief scientific officer atSpark Therapeutics. The IdeS technology has the potential to eliminate anti-AAV antibodies that allow for the extended use of gene therapy in a larger segment of candidates who may have been excluded due to pre-existing or developing neutralizing antibodies and also enable vector re-administration.

The study was conducted by an international collaboration of researchers from Spark Therapeutics in the U.S., and Genethon, the Centre de Recherche des Cordeliers (Inserm, Sorbonne Universit, Universit de Paris) and the National Centre for Scientific Research (CNRS) in France.

AAV-mediated gene therapy allows for the treatment of a growing number of diseases in patients today, however the presence of neutralizing anti-AAV antibodies can lead to limitations of this technology. Specifically, neutralizing anti-AAV IgG pre-exist in up to seventy percent of the population and block the entry of viral vector particles in a given target tissue. Furthermore, high-titer anti-AAV antibody levels usually develop following vector administration and persist long-term thereafter, preventing vector re-administration. To date, researchers have been limited in their ability to bypass the neutralizing activity of anti-AAV IgG.

Study FindingsThe study demonstrated that treatment with the IgG-degrading enzyme IdeS, an endopeptidase from Streptococcus pyogenes that specifically hydrolyses human IgG, resulted in a rapid and transient elimination of neutralizing anti-AAV IgG and restored gene therapy efficacy. IdeS is an endopeptidase able to degrade circulating IgG that is currently being tested in transplant patients.

Researchers demonstrated efficacy in vivo using animal models of liver gene transfer, including hemophilia A and B. Hemophilia is a rare genetic bleeding disorder that causes a delay in clot formation as a result of a deficiency in coagulation factor VIII or IX for hemophilia A or B, respectively. In both mice and non-human primates with neutralizing anti-AAV IgG, IdeS treatment prior to the injection of AAV vectors eliminated neutralizing IgG and rescued the expression of the factor VIII or IX in hepatocytes.

Furthermore, administration of AAV vectors systematically induces a neutralizing anti-AAV immune response, making gene therapy inefficient upon subsequent injections of AAV vectors. The study also demonstrated that treatment with IdeS restores the efficacy of the re-administration of AAV vectors, allowing for efficient transgene expression in non-human primates. The research shows that IdeS allows the repeated administration of AAV vectors by blocking the neutralizing activity of anti-AAV IgG in small and large animal models.

Additional studies in the field of gene therapy have the potential to translate these findings to human trials, with the goal of opening a therapeutic window for patients with neutralizing anti-AAV antibodies. Spark will assess and investigate the potential impact of the IdeS technology on its current gene therapy programs and potential applications in the future.

About Spark Therapeutics AtSpark Therapeutics, a fully integrated, commercial company committed to discovering, developing and delivering gene therapies, we challengethe inevitability of genetic diseases,includingblindness, hemophilia, lysosomal storage disorders and neurodegenerative diseases.We currently have four programs in clinical trials.At Spark, a member of the Roche Group, we see the path to a world where no life is limited by genetic disease. For more information, visit http://www.sparktx.com, and follow us on Twitter and LinkedIn.

Media Contact:Kevin Giordanocommunications@sparktx.com (215) 294-9942

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Study Demonstrating Role of IdeS in Enabling of Gene Therapy in the Presence of Neutralizing Anti-AAV Antibodies Published in Nature Medicine -...

Forbion has led a $62.5 million round for Prilenia Therapeutics to fund two late-stage trials in Huntingtons disease and amyotrophic lateral sclerosis. Michael Hayden, the former Teva R&D chief whos been serving as chairman, will now take over as CEO to oversee the program for pridopidine, which agonizes the sigma-1 receptor (S1R). Morningside and Sectoral Asset Management also joined, as did Talisman Capital Partners and Genworks 2.

Australias CSL Behring is teaming up with Seattle Childrens Research Institute to develop stem cell gene therapies for rare primary immunodeficiency diseases, starting with Wiskott-Aldrich Syndrome and X-linked Agammaglobulinemia. They are among 400 primary immunodeficiency diseases, in which the human immune system is dysfunctional. Expanding our gene therapy portfolio into an area of immunology well known to CSL exemplifies how we are strategically growing our capabilities in this strategic scientific platform and are collaborating with world class institutions to access innovation with the potential to vastly improve patients lives, noted CSL R&D chief Bill Mezzanotte.

Hyloris Pharmaceuticals, a Belgian company dedicated to reformulating well-known drugs, is looking to tap the public market by listing on Euronext Brussels. The IPO is expected to provide us with the resources needed to finance the development of our existing portfolio of product candidates, as well as establish a commercial infrastructure in the United States for our IV Cardiovascular portfolio (excl. Sotalol IV, which is commercialized through a partner), where we will focus on addressing prescribers in a cost-efficient manner by concentrating on specialized care facilities such as hospitals, CEO Stijn Van Rompay said in a statement.

GHO Capital has put the $1 billion-plus fund it closed at the end of last year to use, buying X-Chem froman affiliate of The Carlyle Group and Hellman & Friedman. The company specializes in DNA-Encoded Library (DEL)-based discovery services and has licensed over 70 research programs to biopharma partners over the years.Matt Clark, a co-founder and the current SVP of chemistry, will replace Rick Wagner as CEO.

Dublin-based Avectas has enlisted Scott Simons lab at UC Davis to characterize cells engineered on its platform, with the goal of informing the development of next-gen cell therapies. A major focus of our group is to understand how chemical and mechanical forces acting on immune cells enable them to localize at sites of inflammation, Simon said in a statement. The partnership with Avectas will help us evaluate how these same forces play a role to delivering mRNA and proteins to immune cells and thereby extend their therapeutic applications.

Irelands Shorla Pharma has closed its Series A at $8.3 million to advance a slate of drugs for rare, orphan and pediatric cancers. Seroba Life Sciences led the round, which featured other local investors as well as family offices in Canada.

Christian Angermayer, founder of the mental health and psychedelics biotech ATAI, is trying to bring the Australian biotech Bionomics and its PTSD drug back from the near-dead. Bionomics stock flatlined to $0.04 after the drugs failure in a Phase II trial, but the company, which has also partnered with Merck on Alzheimers, has since reformulated the drug, and Angermayer is betting it might now work. His firm Apeiron put down $5 million and underwrote $15 million in funding to put the compound back into trials.

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Forbion leads $62.5M round for neuro startup as ex-Teva R&D chief takes control; CSL Behring inks gene therapy pact in immunology - Endpoints News

Radiation, chemotherapy and surgery dont cut it against glioblastoma, an aggressive type of brain cancer that often recurs with a vengeance. Ziopharm is working on a remote-controlled gene therapy to buy these patients more timeand early data show it extended patients lives by more than a year.

The company tested the treatment, dubbed Controlled IL-12, in 95 patients as a monotherapy in two studies and in combination with a PD-1 inhibitor in a third study. After finding that the treatment worked best in six patients who took low doses of dexamethasonea steroid commonly prescribed after brain tumor removal surgeryZiopharm tested it in that exact patient population, adding 36 patients in an expansion study. The treatment helped those patients live a median of 16.2 months, an improvement on the 12.7-month survival rate from the main trial, which tested the treatment in 38 patients who took varying amounts of the steroid.

Sixteen months is very, very encouraging, Ziopharm CEO Laurence Cooper, M.D., Ph.D., told FierceBiotech. Those four months may not sound like a lot to me and you, but those four months might represent getting to a wedding or a graduation. Frankly, those four months are 30% more life, he added, referring to historical survival rates for glioblastoma, which top out at 12 months but could be as short as six months.

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A substudy testing Controlled IL-12 with Bristol Myers Squibbs Opdivo is still in its early days, but signs are encouraging, with half of the patients still alive an average of 8.3 months into treatment. And thats not allinvestigators found that one patient in each study had their tumors shrink, bringing the total partial responses across the three studies to five.

Observing responses in brain tumors in the setting of recurrence is unusual and highly encouraging, and, along with the survival data, highlight the potential of [Controlled IL-12] for the treatment of [recurrent glioblastoma], said Antonio Chiocca, M.D., Ph.D., a trial investigator and professor of neurosurgery at Harvard Medical School.

Some patients did exceptionally well, with one patient in the main study still responding after nearly two years and one patient from the expansion study still responding after 48 weeks. Cooper thinks the studies may turn up more exceptional responders, which could help the company figure out why some patients do better than others and, eventually, help itdevelop drugs that boost survival even more.

RELATED: Treating glioblastoma with a Ziopharm drug and IL-12 gene therapy

Glioblastoma has been so hard to tackle because its a heterogeneous tumor: Its not one set of malignant cells, but really a population of cells that all have different attributes relating to the genetics of the disease, Cooper said. A treatment may take out some of those tumor cells but leave the rest alone.

One of the things thats appealing about IL-12 is that its a weapon that activates T cells, Cooper said.

Controlled IL-12 combines an IL-12 gene therapy with Ziopharms pill, veledimex, which can switch the gene therapy on and off as well as tune it up and down. Patients received one dose of veledimex before undergoing surgery to remove their brain tumor. During the surgery, adenovirus vectors that carry the IL-12 gene were injected directly into the tumors. The patients then took veledimex, which turns on IL-12 production in the tumors, waving down T cells to attack and destroy the cancerous tissue.

Its an ideal approach, Cooper said, because the T cells act like little cellular scalpels, eating away at the tumoreven tendrils of it that have penetrated normal brain tissue, beyond the borders where a surgeon can safely operate.

Veledimex is a crucial piece of the puzzle because of how powerful IL-12 is.

Protein IL-12 has been delivered systemically through intravenous injections back in the day, but the side effects were intolerable because IL-12 activated the immune system globally, Cooper said. The trick to harnessing IL-12 is to be able to regulate it rather than giving it to the whole body and hope the patient survives that encounter.

Even though Ziopharms gene therapy is delivered directly to brain tumors, it is inevitable that IL-12 will seep out into circulation, Cooper said. And thats where the switch comes in.

If we get a call, say, from Chicago saying a patient has a fever and impending cytokine storm, we can guide the treating physician from Boston to hold off on the next mornings dose. And that typically takes care of the problem. The fever goes away and we can restart the veledimex, he said.

Next up, Ziopharm is looking forward to the Opdivo data maturing. It will also finish enrolling a phase 2 study combining its treatment with Sanofi and Regenerons PD-1 blocker Libtayo in the first half of this year, despite the COVID-19 pandemic, Cooper said.

Looking ahead, we will have a continuum of data readouts this year and into next year, showing survival and MRI imaging of the monotherapy and in combination, he added. [They will] allow the company to make a decision about the phase 3 trial. With a sizable cohort of patients about the study, well be able to sit back and say, look: Where do we think we can develop and prove this is a drug?

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ASCO: Ziopharm's IL-12 gene therapy boosts survival in hard-to-treat brain cancer - FierceBiotech

Researchers reveal protospacer adjacent motif mutations (PAM sites) on the NRF2 gene of cancers could be used to guide CRISPR gene editing.

New research suggests a mutation in the NRF2 gene, unique to certain malignant tumours, could be used to enable CRISPR gene editing to be safely targeted towards cancer cells that are resistant to treatment.

This advance addresses a big challenge with using CRISPR in cancer patients, which is ensuring it can distinguish between a tumor cell and a normal cell, said Dr Eric Kmiec, director of Christiana Cares Gene Editing Institute, US, and principal author of the study.

According to a commentary (written by the journal editors) accompanying the paper in the journalMolecular Cancer Research, the process developed by the institute can provide an empirical basis for the use of CRISPR-directed gene therapy in solid tumour cells, and continue to advance the use of this technology closer to clinical implementation.

Kmiec explained that the primary aim of the study was to successfully knock out the NRF2 gene in squamous cell carcinoma tumours, without effecting normal cells. To do this, they used mutations to the NRF2 gene that create a protospacer adjacent motif (PAM site), which is exclusively expressed in tumours, to guide CRISPR gene editing.

According to Kmiec, NRF2 protects tumours from damage caused by chemotherapy and radiation, rendering it resistant to treatment. In their earlier studies, Kmiec and colleagues demonstrated knocking out NRF2 using CRISPR increases sensitivity to chemotherapy. Several other cancers, including oesophageal, head and neck, and certain forms of uterine and bladder cancer, are also frequently protected by the NRF2 gene and have mutations creating PAM sites.

Kmiec revealed that NRF2 mutations show up early in tumour development and can be detected using existing tests. They propose using CRISPR to disable NRF2 early-on in the progression of the tumour could improve the efficacy of conventional treatments and potentially lower the dosages required to shrink tumours.

Lead author Kelly Banas concluded: Without any targeted therapy available for this type of lung cancer, the ability to use CRISPR to safely disarm a key mechanism that allows tumours to grow even when being hit with chemotherapy could be an important advance.

They are now conducting tests to assess the safety of targeting NRF2 in squamous cell tumours on animals, in order to conduct a clinical trial in humans at a later date. Such a trial would test whether using CRISPR to knock out the NRF2 gene in squamous cell carcinoma lung cancer tumours improves the efficacy of conventional chemotherapy and radiation treatments.

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Cancer mutation could be used to target CRISPR therapy - Drug Target Review

Before it even started, ASCO 2020 was one for the books. Held virtually for the first time in its history instead of at Chicagos massive McCormick Place conference center, the American Society of Clinical Oncologys big meeting also shrank from five days to three last weekend.

After following ASCO news from afar, STATs Adam Feuerstein on Wednesday continued in that vein, hosting a virtual chat with three noted oncologists to get their take on the future of cancer therapy. After big news from AstraZeneca in lung cancer, Johnson & Johnson in multiple myeloma, and Allogene in off-the-shelf gene therapy, they paused to reflect on their field and ASCO 2021. Here are some of their observations:

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Recapping ASCO, talking cancer therapy combinations, and looking ahead - STAT

DUBLIN--(BUSINESS WIRE)--The "Global Viral Vector and Plasmid Manufacturing Market: Focus on Vector Type, Application, Disease, 5 Region's Data, 15 Countries' Data, Patent Landscape and Competitive Insights - Analysis and Forecast, 2020-2030" report has been added to ResearchAndMarkets.com's offering.

According to this report the global viral vector and plasmid manufacturing market was valued at $1.16 billion in 2019 and is expected to be $5.86 billion in 2030.

The viral vector and plasmid manufacturing market is expected to grow at a lower double-digit compound annual growth rate in the forecast period 2020-2030. The growing prominence of vector-based gene therapy products and high funding activities in research for the development of novel therapies, coupled with an increasing prevalence of diseases, such as cancer, genetic diseases, and infectious diseases, is prominently driving the growth of the global viral vector and plasmid manufacturing market.

The rising prevalence of diseases has led to an increasing demand for the development of advanced therapies and drugs to meet the needs of the growing patient population. The advent of cell and gene therapy has offered the high potential to treat diseases that are otherwise incurable by conventional treatment modalities. Both therapies encompass the use of vector, as gene delivery vehicles, for the introduction of a therapeutic gene into the target cell in order to provide a cure or remedy to disease. Extensive progress made in gene and cell therapy research since the early 1970s and 1980s has, therefore, accelerated the adoption rate of plasmids and viral vectors for their use in these modern therapies.

Progress made in the field of vaccinology, involving the use of vectors, has further intensified the demand for these vectors. A large number of preclinical and clinical studies evaluating the potential of vectors in these advanced therapies have further displayed promising results. This, in turn, has attracted the attention of investors, making viral vector and plasmid manufacturing market an active area of investment as well as encouraging favorable funding activities from both the private and public sectors.

Currently, the global viral vector and plasmid manufacturing market is witnessing the entry of several contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) that are striving hard to sustain the competition with the main goal to increase the production of vectors that would be both cost-effective and of superior quality. The market is currently dominated by juggernauts, such as Lonza, Thermo Fisher Scientific Inc, Merck KGaA, GE Healthcare, Sartorius AG, and other small-medium enterprises, which offer a wide range of vector manufacturing products and services to the market.

Key Questions Answered:

Market Dynamics

Drivers

Restraints

Opportunities

Companies Profiled

For more information about this report visit https://www.researchandmarkets.com/r/qy82g1

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Insights on the Worldwide Viral Vector and Plasmid Manufacturing Industry to 2030 - Analysis and Forecast - ResearchAndMarkets.com - Business Wire

NEW YORK, June 04, 2020 (GLOBE NEWSWIRE) -- Prevail Therapeutics Inc. (Nasdaq: PRVL), a biotechnology company developing potentially disease-modifying AAV-based gene therapies for patients with neurodegenerative diseases, today announced the appointment of Kira Schwartz, J.D., as the Companys General Counsel. In this new role, Ms. Schwartz will lead all aspects of the Companys legal organization.

We are excited to welcome Kira to Prevail as our general counsel and latest member of our executive team, said Asa Abeliovich, M.D., Ph.D., Founder and Chief Executive Officer of Prevail. Prevail will greatly benefit from Kiras significant expertise as a senior legal counselor within the biopharmaceutical industry. She will play a key role in shaping our internal legal function and advising the Board and leadership team on all legal and corporate governance issues as we continue to advance our AAV gene therapy-based pipeline through the clinic for patients with neurodegenerative diseases.

Prevail is well-positioned to be a leader in developing transformative treatments for patients with neurodegenerative disorders, and I look forward to joining such a mission-driven team at an important point in the Companys growth and development, with anticipated clinical advancements in the year ahead, said Ms. Schwartz.

Prior to joining Prevail, Ms. Schwartz served as Senior Vice President, Associate General Counsel and Assistant Secretary at Allergan plc (formerly Actavis plc), where she led a legal group supporting business development, corporate governance, finance, human resources, supply chain and real estate functions. As Vice President, Associate General Counsel at Actavis, she led Actavis $70.5 billion acquisition of Allergan, Inc. Previously, she held senior leadership positions at Forest Laboratories, Inc. (acquired by Actavis), where she oversaw a variety of projects, including business development, manufacturing and supply chain, R&D and more, and was senior corporate counsel in Pfizer Inc.s business transactions group. Ms. Schwartz started her career at Cleary, Gottlieb, Steen & Hamilton LLP. She received her J.D. from Yale Law School and a B.A. in economics from Tufts University.

About Prevail Therapeutics

Prevail is a gene therapy company leveraging breakthroughs in human genetics with the goal of developing and commercializing disease-modifying AAV-based gene therapies for patients with neurodegenerative diseases. The company is developing PR001 for patients with Parkinsons disease with GBA1 mutations (PD-GBA) and neuronopathic Gaucher disease; PR006 for patients with frontotemporal dementia with GRN mutations (FTD-GRN); and PR004 for patients with certain synucleinopathies.

Prevail was founded by Dr. Asa Abeliovich in 2017, through a collaborative effort with The Silverstein Foundation for Parkinsons with GBA and OrbiMed, and is headquartered in New York, NY.

Media Contact:Mary CarmichaelTen Bridge Communicationsmary@tenbridgecommunications.com617-413-3543

Investor Contact:investors@prevailtherapeutics.com

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Prevail Therapeutics Appoints Kira Schwartz, JD, as General CounselMs. Schwartz brings over 16 years of legal experience in the biopharma industry to...

By 2027, the global gene therapy market is estimated to reach a staggering value of $6.6B. With the number of successfully approved gene therapies increasing, the sector has moved from hype to hope. At the heart of gene therapy lie viral vectors, which are used to transport a gene into a target cell. Here we explore the current bottleneck in viral vector production, why viral vectors still outshine non-viral vector solutions, and what we can expect in the future.

The gene therapy field is gaining momentum. Investments are pouring in. The FDA is estimating that by 2025 it will approve between 10 and 20 cell and gene therapy products every year. This shows that a treatment, which started out as a hype, is now a real hope, says Ratish Krishnan, Associate Director of Cell and Gene Therapy Bioprocessing at MilliporeSigma*.

Today, a number of treatments have been approved, such as Spark Therapeutics LUXTURNA, the first FDA approved in vivo gene therapy, or Novartis Zolgensma, which gained US approval in 2019 and European approval in March 2020.

One of the key ingredients of gene therapies is the viral vector, which is used to transfer a gene of interest into a target cell. The most commonly used vector is that of the adeno-associated virus (AAV). But the manufacturing of viral vectors and scaling up their production remain difficult.

In upstream development, one challenge is the way viral vectors are produced. In a process called transient transfection, plasmids carrying the DNA of interest are introduced into host cells that will produce the viral vectors.

But host cells are commonly grown in adherent cell cultures, which are usually harder to reproduce at a large scale. So to scale-up and achieve high titers of virus particles, researchers are working on growing cells in suspension using large bioreactors instead.

We are facing several challenges at the moment and that is what keeps us on our toes, Krishnan adds. In upstream development, there is a desire to move towards suspension. Most processes use transient transfection methods using plasmids and the transfection step at a production scale of 500L or 2000L is extremely challenging.

In downstream development, researchers are studying the purity of capsids. The capsid is the protective shell of the virus enclosing the gene of interest. Related to this is an important discussion on the purity of viral vectors.

When you produce vectors, you will generally have a population of empty capsids, which is the viral AAV assembly without the genetic material inside, or partially-full capsids with only part of the DNA inside, Krishnan explains. We have to better understand the role of empty capsids inside the body. Are they needed as immune decoys or are they strictly considered impurities? In theory, you only need the ones with all the DNA inside, the full capsids.

But researchers have yet to discover the correct percentage of full capsids in a drug substance or product, Krishnan says. We dont have the answer yet. Typically, the strategy leans towards the enrichment of a percentage of full capsids as high as possible, while taking into account the data from clinical trials.

Questions about purity are difficult to answer because there is little or no regulatory guidance. For instance, compared to monoclonal antibodies (mAbs) for which the regulatory environment is well understood, the regulatory landscape for gene therapies remains largely unclear.

Through decades of research, mAb production also works through well-established and standardized platforms, whereas viral vectors are still in their infancy and cannot be produced using platform technologies yet although much is being done in this field and they are catching up fast.

Because of their longstanding history, we already have a lot of knowledge and research about mAbs, Krishnan explains. Lets say I want to start a biotech company or a CDMO that develops mAbs. I can rely on existing templates and get up and running much quicker than if I were developing viral vectors.

AAVs come in many different serotypes distinguishable strains which impact platform development. The scale-up is also challenging since the indications can be strikingly contrasting. For example, ocular indications need smaller viral drug substances compared to a muscular indication.

Manufacturing mAbs is better understood than manufacturing viral vectors. Viruses are a whole lot bigger and can be more complex than antibodies. While antibodies usually have a size around 10 nm, AAVs measure around 20nm and Lentiviruses around 100nm in size. Not only are antibodies produced at a larger scale than viral vectors, but their scalability is also more predictable due to the established platform technologies.

Despite these challenges, the increase in popularity, investments flooding in, and the promise of essential cures have led to a bottleneck in viral vector production for gene therapies. But many companies working in the gene therapy field are small or emerging biotechs that do not have the necessary resources and expertise in-house to tackle the challenges of viral vector production.

Lacking the facilities to do it themselves, small and emerging biotechs therefore turn to experienced contract development and manufacturing organizations (CDMOs), such as Merck BioReliance, to produce their gene therapies.

There are only a handful of CDMOs that have the capability and expertise to take on the complexities of gene therapy projects, Krishnan says. But there is currently a bottleneck in manufacturing slots. Manufacturing facilities can only work 24 hours a day, and if you are a small company and a CDMO has other clients waiting in line before you to have their therapies manufactured, you have no other option but to wait.

The problem with waiting, of course, is that the biotech runs the risk of falling behind its competition. Krishnan emphasizes, time is of the essence in gene therapy. There is no silver medal for developing a therapy for the same indication.

The key, says Krishnan, lies in much planning and close engagement with the CDMO partner. Biotechs should do an analysis of what they can perform in-house versus what they have to outsource early on. Engaging a CDMO is the route you want to take.

With decades of experience, Merck can support its biotech sponsors all the way to the clinic. We are big on the concept of integrated solutions, Krishnan explains. From clone to clinic to commercialization, Merck has the expertise, knowledge network, product, and services to help guide any customer to the finish line. We have the CDMO expertise with BioReliance, with testing services, gene therapy expertise, and regulatory support.

To circumvent the manufacturing bottleneck for viral vectors, some biotechs are looking at non-viral vector solutions for gene therapies. While traditional gene therapies use a viral vector, like AAV, to transfer a gene of interest into the patient, non-viral gene therapy deploys an alternative delivery system for the gene of interest.

Examples for non-viral delivery systems include physical force to deliver the gene through the cell membrane; injecting the gene with a needle into the target region; electroporation, which uses an electric current to produce pores in the cell membrane through which the gene can be inserted into the cell; and chemical vectors, such as lipid-, polymer-, or peptide-based particles.

Nevertheless, viral vectors, such as the AAV, remain the preferred path for most companies. The efficiency of delivery for non-viral vectors remains questionable. This means that there might be reactions in the immune system that get triggered, eliciting a dangerous, adverse response. AAVs, on the other hand, are well-engineered and safe, despite being novel.

Viral vectors have recently demonstrated success, Krishnan adds. Scientists are making advances in the non-viral area of gene therapy but they also come with a unique set of challenges. Questions, such as how do they interact with serum components in the body, how do they involve the immune system before reaching the target tissue, how do they interact with the surfaces of cells, remain.

Despite unaddressed challenges, gene therapy has definitely shifted from being a hope to carrying an expectation. This is reflected in the number of investments pouring into the sector.

Big pharma and biotech companies are heavily investing their resources into gene therapy, Krishnan says. Typically, companies have vaccines or mAbs in their portfolio. Now, gene therapy is becoming a major modality of interest as well.

While we are still far away from reaching the smooth manufacturing processes we have in place for antibodies, many companies are also looking into platform approaches for gene therapy. We would take a quantum leap if we developed a platform approach for upstream and downstream processes. That would significantly reduce the time to the clinic. Platform approaches are definitely being explored, Krishnan adds.

Vendors like Merck are playing a big role in developing fit-for-purpose products for gene therapies, Krishnan says. At the R&D level, researchers are also working on advances in capsid engineering. We already have synthetic capsids, and there are other tremendous advancements in capsid engineering, design, and purity, which are going to continue to evolve.

But, as Krishnan puts it, We are running a marathon at sprint speed. The journey is exciting and challenging, identical to the ride on a rollercoaster, but we are barely even at the tip of the iceberg. There are patients waiting for life-saving treatment, so gene therapies will definitely continue to be in the limelight, and for good reason.

Are you fighting to solve the bottleneck in viral vector production? Get in touch with the expert team at Merck and view their webinar on this topic!

*The life science business of Merck operates as MilliporeSigma in the U.S. and Canada.

Images via Shutterstock.com and Elena Resko

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The Roller Coaster of Gene Therapy... - Labiotech.eu