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Tackling the hurdle of tumor formation in stem cell therapies – EurekAlert

Posted: June 4, 2024 at 2:48 am

image:

A safer regenerative medicine process that removes the risk of tumor formation.

Credit: Atsushi Intoh

Ikoma, Japan Pluripotent stem cells (PSCs) are a type of stem cells capable of developing into various cell types. Over the past few decades, scientists have been working towards the development of therapies using PSCs. Thanks to their unique ability to self-renew and differentiate (mature) into virtually any given type of tissue, PSCs could be used to repair organs that have been irreversibly damaged by age, trauma, or disease.

However, despite extensive efforts, regenerative therapies involving PSCs still have many hurdles to overcome. One being the formation of tumors (via the process of tumorigenesis) after the transplantation of PSCs. Once the PSCs differentiate into a specific type for stem cell therapy, there is a high probability of tumor formation after differentiated stem cells are introduced to the target organ. For the success of PSC-based therapies, the need of the hour is to minimize the risk of tumorigenesis by identifying potentially problematic cells in cultures, prior to transplantation.

Against this backdrop, a research team led by Atsushi Intoh and Akira Kurisaki from Nara Institute of Science and Technology, Japan, has recently achieved a breakthrough discovery regarding stem cell therapy and tumorigenesis. Our findings present advancements that could bridge the gap between stem cell research and clinical application, says Intoh, talking about the potential of their findings. Their study was published in Stem Cells Translational Medicine and focuses on a membrane protein called EPHA2, which was previously found to be elevated in PSCs prior to differentiation by the team.

Through several experiments involving both mouse and human stem cell cultures, the researchers gained insights into the role of EPHA2 in preserving the potency of PSCs to develop into several cell types. They found that EPHA2 in stem cells is co-expressed with OCT4a transcription factor protein which controls the expression of genes which are critically involved in the differentiation of embryonic stem cells. Interestingly, when the EPHA2 gene was knocked down from the cells, cultured stem cells spontaneously differentiated. These results suggest that EPHA2 plays a central role in keeping stem cells in an undifferentiated state.

The researchers thus theorized that EPHA2-expressing stem cells, which would fail to differentiate, might be responsible for tumorigenesis upon transplantation into the target organ.

To test this hypothesis, the researchers prepared PSC cultures and artificially induced their differentiation into liver cells. Using a magnetic antibody targeting EPHA2, they extracted EPHA2-positive cells from a group of cultures prior to transplantation into mice. Interestingly, the formation of tumors in mice receiving transplants from cultures from which EPHA2 had been removed was vastly suppressed.

Taken together, these results point to the importance of EPHA2 in emerging stem cell-based therapies. EPHA2 conclusively emerges as a potential marker for selecting undifferentiated stem cells, providing a valuable method to decrease tumorigenesis risks after stem cell transplantation in regenerative treatments, remarks Kurisaki.

Further in-depth studies on this protein may lead to the development of protocols that make PSCs safer to use. Luckily, however, these findings pave the way towards a future where we will be able to finally restore damaged organs and even overcome degenerative conditions.

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Resource

Title: EPHA2 is a novel cell surface marker of OCT4-positive undifferentiated cells during the differentiation of mouse and human pluripotent stem cells.

Authors: Atsushi Intoh, Kanako Watanabe-Susaki, Taku Kato, Hibiki Kiritani, Akira Kurisaki

Journal: Stem Cells Translational Medicine

DOI: 10.1093/stcltm/szae036

Information about Laboratory for Stem Cell Technologies can be found at the following website: https://bsw3.naist.jp/eng/courses/courses215.html

About Nara Institute of Science and Technology (NAIST)

Established in 1991, Nara Institute of Science and Technology (NAIST) is a national university located in Kansai Science City, Japan. In 2018, NAIST underwent an organizational transformation to promote and continue interdisciplinary research in the fields of biological sciences, materials science, and information science. Known as one of the most prestigious research institutions in Japan, NAIST lays a strong emphasis on integrated research and collaborative co-creation with diverse stakeholders. NAIST envisions conducting cutting-edge research in frontier areas and training students to become tomorrow's leaders in science and technology.

Stem Cells Translational Medicine

Experimental study

Animals

EPHA2 is a novel cell surface marker of OCT4-positive undifferentiated cells during the differentiation of mouse and human pluripotent stem cells.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Acorn Biolabs nabs $11M Series A to boost access to regenerative medicine via cell preservation – BetaKit – Canadian Startup News

Posted: June 4, 2024 at 2:48 am

Biotech startup aims to unlock hair regrowth, skin rejuvenation, disease treatment by preserving cells.

Toronto-based biotechnology startup Acorn Biolabs, which helps customers freeze their stem cells in preparation for cell-based regenerative medicine treatments, has announced approximately $11 million CAD ($8 million USD) in Series A funding across multiple closings.

The all-equity, all-primary round was led by new backer Merz Aesthetics with support from Telus Global Ventures, MDE Investments, The Leslie Group, Lee Li Holdings, and several undisclosed physicians in the aesthetics, orthopedic, and longevity fields.

Acorn claims to offer the worlds first non-invasive, [hair] follicle-based cell cryopreservation service.

Founded in 2017, Acorn aims to provide clients with access to personalized regenerative medicine through what it claims is the worlds first non-invasive, [hair] follicle-based cell cryopreservation service and patented cell-based treatments from patients hair follicle cells. By preserving cells, the startup hopes to unlock the possibility of future hair regrowth, skin rejuvenation, injury recovery, and disease treatment through regenerative medicine.

Acorn plans to use this capital to expand its commercial footprint and develop cosmetic offerings. Acorn co-founder and CEO Drew Taylor told BetaKit he believes that since its launch in North America over a year ago, Acorn has proven its model in hair follicle-based stem cell banking. He expects the startups business to accelerate following investments in direct-to-consumer advertising and in-clinic promotion.

We are entering a pivotal time in our history where well launch the first, personalized cosmetic skin and hair product made specially leveraging the persons own hair follicles, said Taylor. We believe the market is primed for this type of personalized approach based on the positive reception weve received to date.

Taylor declined to share when the startups Series A round closed. He also declined to share the companys valuation but claimed it was higher than Acorns seed financing. With this latest capital, Acorn has now raised more than $13.6 million CAD in total funding to date.

The announcement of Acorns Series A round comes more than five years after Acorn raised $3.3 million in seed funding from Real Ventures, Globalive Technology, Pool Global Partners, and Epic Capital Management to fuel its launch. In 2021, Acorn closed another $250,000 from MCI OneHealth, now Healwell AI.

RELATED: Fuelled by Well Health partnership, Healwell looks to apply AI to preventative care

Last year, Acorn launched its stem cell banking service in Canada and the United States.

Acorn customers can visit participating clinicsoften dermatologists or plastic surgeonsand have a clinician collect a sample of their hair follicles, which Acorn then preserves at their labs indefinitely until they are required again. Clients pay an annual subscription fee for this service. In 2023, Taylor said Acorn saw cumulative patient growth of more than 10 percent monthly.

Taylor claimed that Acorn and its 21-person team possess a true first-movers advantage in the category of stem cell cryopreservation leveraging hair follicles as the source.The next step in the companys evolution involves creating topical skin and hair care products, which Acorn plans to make available through those same clinics.

Taylor said Acorn will also expand its commercial operation partner sites in North America and hire a sales team to support clinics in dermatology and plastic surgery, as it gears up to launch its first skin and hair care product in the next year.

RELATED: Biotech startup Noa Therapeutics raises $2.2 million in pre-seed funding

He acknowledged that the skin and hair care markets are both quite large and competitive, but claimed that no other company currently sells a personalized skin or hair care product like the one Acorn plans to launch. Taylor noted that other offerings in the topical cosmetic space leverage donated tissues from other humans or derived from plants.

In a statement, Merz Aesthetics chief corporate development officer Jon Parrish noted that regenerative aesthetics aims to stimulate the bodys own systems to repair and restore the structure and integrity of aging skin.

We are looking to invest in opportunities that lie at the intersection of regenerative aesthetics and personalized medicine and our investment in Acorn directly aligns with this strategy, he added.

Feature image courtesy Acorn Biolabs.

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Global Biopreservation Market Forecast Report 2024-2029: Advances in Biobanking and Growing Trend of Conserving … – GlobeNewswire

Posted: June 4, 2024 at 2:48 am

Dublin, June 03, 2024 (GLOBE NEWSWIRE) -- The "Global Biopreservation Market by Product (Media [Cryopreservation, Hypothermic]), Equipment (Freezers, Refrigerators, Incubators, Centrifuge, Accessories), Biospecimen (Tissues, Organs, Stem Cells), Application (Research, Therapeutic) - Forecast to 2029" report has been added to ResearchAndMarkets.com's offering.

The global Biopreservation market is projected to reach USD 7.1 billion by 2029 from USD 4.4 billion in 2024, at a CAGR of 9.8% during the forecast period. The growth of this market is majorly driven by rise in demand for preserving biological materials in healthcare, research, and industrial application, growing prevalence of chronic diseases, and technological advancements. However, technical challenges, quality control, energy consumption and environmental impact could restrain the growth of the Biopreservation market.

Biopreservation Media segment accounted for the highest market share in the Biopreservation market, by product, during the forecast period.

Based on product, the Biopreservation market is segmented into biopreservation media, biopreservation equipment, and accessories. The biopreservation media segment accounted for the largest market share in 2023. This is attributed to the growing advancements in biotechnology and pharmaceutical companies, rise in demand for regenerative medicine, globalization of clinical trials, and expansion of cell & gene therapies.

Human Tissue Samples accounted for the larger market share in the Biopreservation market, by biospecimen, during the forecast period.

The Biopreservation market is segmented into human tissue samples, organs, stem cells, and other biospecimens. The human tissue samples segment accounted for the largest market share in 2023. This can be attributed to the rise in expansion of biobanking initiatives, growth in personalized medicine, and growing investments in biomedical research.

Biobanks accounted for the highest CAGR during the forecast period.

Based on the end user, the Biopreservation market is segmented biobanks, gene banks, hospitals, and other end users such as research institutes and universities, pharmaceutical companies, and contract research organizations. The biobanks segment accounted for the largest share of the biopreservation market in 2023. Growth in clinical research & trials, increasing collaborative research initiatives, and rise in funding from the government are supporting the growth of this end-user segment.

The North America segment accounted for the highest market share in the Biopreservation market, by region, during the forecast period.

Based on the region, the Biopreservation market is divided into North America, Europe, the Asia Pacific, Latin America, the Middle East & Africa, and GCC. North America region accounted for the largest share of the global Biopreservation market in 2023. This large share of North America is due to the strong healthcare system, presence of leading biotech and pharmaceutical companies, and innovation in cryopreservation and cryobanking.

The report provides insights on the following:

Key Attributes:

Key Topics Covered:

Executive Summary

Premium Insights

Key Market Dynamics

Drivers

Restraints

Opportunities

Challenges

Companies Featured

For more information about this report visit https://www.researchandmarkets.com/r/sfoh9k

About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends.

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Promising new results for potential herpes cure: HealthLink – KING5.com

Posted: June 4, 2024 at 2:48 am

SEATTLE It is a virus that's been ailing humans for millions of years, but to this day, there has been no absolute cure.

Virologistsat Fred Hutchinson Cancer Center in Seattle believe they're on their way to finding one through gene therapy after pre-clinical models showed it reduced up to 90 percent of the viral infection in tests.

"We're working on trying to develop new, gene therapy-based cures. Not just to treat these viruses but actually to cure them," saidDr. Keith Jerome, a professor in the Vaccine and Infectious Disease Division at Fred Hutch and one of the researchers of the study.

Jerome's research specialty is on persistent viruses like HIV, Hepatitis B, and herpes simplex virus.

"We're working on trying to develop new, gene therapy-based cures. Not just to treat these viruses but actually to cure them," Jerome said.

Herpes simplex virus 1, or HSV 1, mostly shows up as painful blisters around the mouth, commonly referred to as "cold sores," but it can also infect the genital region, according to Jerome.

"These are really common. I mean over half the people in the world have one or the other or both, so they're very common infections," Jerome said.

According to the latest available data from theWorld Health Organization, 3.7 billion people under age 50 worldwide have HSV 1. An estimated 491 million people between age 15 and 49, have herpes simplex 2, or HSV 2, the virus that causes genital herpes infections.

While there are existing and effective anti-viral herpes treatments available today, Jerome said they don't solve the problem. He said the herpes virus, in particular, buries itself deep into nerve cells and can go dormant.

"The viruses hang out there in the form that stays for life," Jerome said.

So while anti-virals are at-the-moment treatments, there has not yet been an outright cure.

"That long-lived form in the nerves is not even touched. So it can always come back and always start new episodes," Jerome said.

Jerome and his team believe they're on their way to finding a cure by way of gene therapy to get rid of herpes infection for good.

Their findings,publishedin the journal Nature Communications in May, showed they were able to eliminate at least 90 percent of the virus from nerves in animal testing models.

"What we're doing with our gene therapy is actually sending a protein into those nerve cells that actually looks for the virus and basically snips it just like scissors, cuts it in a couple of places, and the body recognizes, it suddenly can see that, and gets rid of it.

The gene therapy also significantly lowered the frequency and amount of viral shedding in animal testing and worked as effectively, if not more, for genital HSV 1 infections, according to Jerome.

"And that's the late, long-lived form we're actually getting rid of," Jerome said.

It's a long sought-after cure, not only because of its prevalence but the stress, even stigma, it causes.

"For some people, it is not a big deal. For other people, it's an enormous deal. And that's each person's lived experience. What we want to do is offer a tool that says if this really matters to you, we can help make your life better," Jerome said.

While the pre-clinical phase showed promising results, the gene therapy has yet to enter clinical trials and is not available as a treatment now.

If approved, Jerome sees the treatment administered as an injection.

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Taking a frothy risk to advance gene therapy – Fred Hutchinson Cancer Center

Posted: June 4, 2024 at 2:48 am

Inspiration sparked by shaving

Stephan co-founded Tidal Therapeutics to help commercialize his immune-cell programming nanoparticles (acquired by Sanofi in 2022). His lab needed a new direction, and inspiration struck one morning as he watched his freshly sprayed shaving foam expand in his palm.

I thought, Let's explore foam, Stephan said. Maybe we can make a formulation of foam that is not like the foam in in our shaving foam, but something that is biocompatible, to deliver therapeutics.

The froth had properties that would be attractive in a drug-delivery vehicle. Its volume started small, but puffed up. The foam stayed where it was sprayed, and didnt slide away. These characteristics could help get a therapeutic into contact with more critical cells while also ensuring that it didnt slip away.

Trying new substances or approaches that come from things in everyday life that you wouldn't necessarily associate in medical applications is sometimes a really interesting way to drive down costs and deliver drugs more easily, Fitzgerald said. But it was definitely a little bit out of my wheelhouse.

Foam-as-medical-delivery method isnt without precedent, Stephan noted. Foam-based delivery already enhances certain applications like delivery of hemorrhoid medication and intra-uterine imaging.

But could foam enhance gene therapy?

To create a bio-compatible foam, Stephan and his team initially took inspiration from the food industry.

Cocktails, ice cream, yogurt: they know how to make things foamy, he said.

Stephan Lab members, including staff scientist Sirka Stephan, PhD, started experimenting with ingredients available from the pantry store, he said.

Importantly, these materials are dead cheap, Stephan said. Theyre available for pennies. Theyre manufactured at large scale, and because theyre already used for pharmaceutical applications like coating tablets theyre available pharmaceutical-grade.

The scientists formulated a solution of methylcellulose (a food binder) and xanthan gum (a food thickener) that, when aerated using two lab syringes, bubbles into an easy-to-apply froth.

But did it have the potential to improve gene therapy?

We started with a lot of hypotheses in terms of, could foam potentially concentrate our gene therapy, keep it more localized, and help it stay in the tissue where we wanted to adhere? Fitzgerald said. My job was to do the experiments to prove the hypotheses.

Foam has certain properties that make it an attractive drug-delivery vehicle. Its more than tightly packed air bubbles: In a foam, the bubbles are separated and surrounded by incredibly thin layers of continuous liquid, called lamellae. Active ingredients become highly concentrated in these lamellae, which allows foam to deliver highly concentrated doses of medicine to large areas, even if the total dose is small.

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Ultragenyx gene therapy for rare liver ailment succeeds in late-stage trial – STAT

Posted: June 4, 2024 at 2:48 am

Ultragenyx said Thursday afternoon that its gene therapy for a rare liver ailment, glycogen disease type 1A, succeeded in a Phase 3 trial, setting up a potential approval.

Patients with GSD1a, as the condition is often known, have a genetic mutation that prevents them from adequately maintaining blood sugar levels. Once considered fatal, GSD1a can now be controlled with regular doses of cornstarch. But if patients miss a dose, there can be significant, even life-threatening, complications.

In the 49-person, randomized study, patients who received the Ultragenyx drug were able to take 41% less cornstarch after 48 weeks than they did at the start. Patients on placebo took only 10% less. The difference was statistically significant. Five patients were not included in the analysis, as three dropped out and the company didnt have 48-week data from two.

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How cell and gene therapy are evolving – Clinical Trials Arena

Posted: June 4, 2024 at 2:48 am

The progress of advanced therapeutics in recent years, especially in oncology, have been so promising many are starting to use the term cure when talking about some types of cancer. Despite complex manufacturing processes, multiple cell and gene therapies are providing front-line treatment options, with others continuing to move closer to front-line.

In many cases, producing a cell therapy involves modifying primary immune cells to recognize, seek out, and attack specific cancer cells, which can co-opt immunosuppressive mechanisms to evade the bodys immune defenses.

As scientific understanding develops in parallel with technological advances, the next generation of cell and gene therapies addressing a wide array of conditions and diseases are expected to be developed and commercially approved. Oncology is the dominant therapy area, which is widely expected to continue in the years ahead. Within the next decade, treatment options are also understood to be possible for central nervous system conditions and immunology patients.

Recent breakthroughs in cell and gene therapy build on research knowledge and expertise that span decades. The first chimeric antigen receptor (CAR) T-cell therapies were tested for oncology in the late 1990s and early 2000s. These early CAR-T cell therapies did not show the proper durability for eliminating cancer, so considerable efforts were focused on increasing that durability. The turning point came in 2012, when several manuscripts were published describing the first CAR-T patients who were in remission because of the therapy. This was followed by what is now seen as a pivotal moment in the field: the treatment of the first pediatric patient, Emily Whitehead.

After the 2012 milestones, the intensity of cell therapy development increased and culminated in a pivotal year, 2017, when the U.S. Food and Drug Administration (FDA) approved the first CAR-T therapy, Kymriah. Later in 2017, the European Medicines Agency (EMA) approved its first CAR-T therapy, Yescarta. Between 2017 and the end of 2022, a total of six therapy products were approved by the FDA.1

The growth of commercial cell therapies continues. In 2023 alone, there were eight U.S. cell therapy commercial approvals by FDA. Depending on progress in 2024, the U.S. may see more than ten products approved.

The advanced therapy preclinical and clinical pipeline also continues to show promising growth. There are approximately 1,800 active clinical trials worldwide, with 60% having at least one clinical site in the U.S.2 This seems to suggest the field will continue to see commercial approvals. In cell therapy, multiple products address blood cancers, including multiple myeloma, leukemias, and lymphomas. The field hit another crucial milestone in February 2024 when the FDA approved the first tumor-infiltrating lymphocyte (TIL) therapy for solid tumors.2

This first-line TIL therapy has been designed to treat melanoma. As with CAR T-cell therapies, Iovance Biotherapeutics Amtagvi involves taking cells from the patients body and enhancing them externally before re-administering them to the patient, where they then attack tumor cells.

Weve already proven that CAR-T works in leukemia and lymphoma, now were starting to prove that new technologies harnessing neoantigens, TIL, CAR-T, and others can now be applied to the next therapeutic hurdle of solid tumors, explains Dr. Phil Vanek, chief technology officer at Gamma Biosciences.

There remains a supply and demand imbalance in the advanced therapies space, specifically in cell therapies that target cancer. A survey of 17 clinical centers in the U.S. led by Dr. Yin Lin at the Mayo Clinic in Minnesota, the median waiting time for patients to receive a commercial CAR-T therapy was six months.

Survey results revealed in 2022 that only 25% of patients received the commercial CAR-T therapy for which they qualified, and another 25% of patients joined a different CAR-T clinical trial because of their inability to access their preferred commercial CAR-T therapy.3 The remaining 50% of patients either entered an alternative type of clinical trial or moved into a hospice and died.3

Commercial cell therapy costs run into the hundreds of thousands of dollars, and this presents a potential barrier to adequate patient access. Matthew Hewitt, CTO for CGT and Biologics at Charles River Laboratories (CRL), emphasizes the need to prioritize

identification and commercialization of promising new therapies. Its important for these therapeutic developers to work with partners and help them think through important considerations about manufacturing, costs, and regulatory approval.

While everyone agrees we need to address costs, first we need commercial therapies then we can continue to work on improving them from a cost perspective, he says. If you look at history, the pharma space has a pretty good track record of innovating our way out of problems.

There are a lot of technologies in development and coming to the market which can help bridge that gap, adds Hewitt.

Development timelines for cell therapies have shortened notably in recent years. In previous generations, it was common to have timelines of ten to 12 years for a biologic product to progress from discovery to clinical trials and commercial authorization. But timeframes for CAR-T therapies are substantially shorter.

The first CAR-T was approved in just a few short years from the first therapeutic trials, all the way through commercialization. That shortened our cycle time for development and were still working to improve it, says Vanek.

Despite the pharma industrys historic reputation for being slow-moving, Vanek explains that the rapid pace of development of CAR-T therapies forced the industry to adapt processes and manufacturing technologies. One of the biggest challenges was production being heavily reliant on tools and technologies built for the bioprocessing industry.

The industry was building the plane while we were flying it. We were scrambling to keep up. But that was a good thing, adds Vanek. Clinical success must be at the heart of everything. We can anticipate what might be successful. But when you see a binary clinical success, like a CAR-T therapy, where people go into remission and remain that way, that was a real wake-up call to say: This therapeutic modality is real, its here, its now. We must adapt how we make these things to make them widely available.

To meet demands for pace and scale, life sciences and tech companies have built equipment and analytical technologies that combine manufacturing and analysis to drive greater efficiencies in development and production. As a direct result, the industry has learned how to consistently make many different types of cell and gene therapies.

Weve taken out a lot of the variability in manufacturing to make these therapies much more robustly and reproducibly, says Vanek. Weve also reduced a lot of the therapeutic and regulatory risk by removing animal component materials and adding well-characterized raw materials. Weve worked out the supply chain in terms of receipt of materials, freezing cells and thawing, and keeping cells throughout the manufacturing workflow both viable and healthy.

In terms of tracking cells for autologous patients, were using a much more significant chain of custody and chain of identity capability to strengthen the entire supply chain of cell and gene therapy manufacturing.

As we reduce the cost of manufacturing, there will be pressure in the industry to make these therapies more affordable and more widely available.

There is much optimism within the industry about the future, with thousands more cell and gene therapies undergoing clinical trials. Despite many remaining challenges, the industry clearly wants to develop the necessary solutions.

We know autologous works, explains Hewitt. So, we should also be pushing forward better autologous development of therapeutics, as well as better equipment to allow us to manufacture these therapies in a larger scale more cheaply without compromising safety and quality.

Built on an understanding of oncology, cell and gene therapies could one day provide effective treatments for a range of infectious diseases and conditions such as diabetes, as well as improve the health of neurological patients. There is also much excitement surrounding therapies in the autoimmune space, as well as the ongoing discoveries of new cell types that create further opportunities.

Looking at the autoimmune space, were seeing some really good data there, adds Hewitt. IPSCs (induced pluripotent stem cells) should also be in the conversation. These are cells with the ability to become any cell type with the right stimuli. They have applications both within and outside of oncology, and more going into regenerative medicine.

Also, on the allogeneic side, most programs are using donors to supply their starting material. Campaigns to find good donors can be very expensive and time-consuming. By moving over to an IPSC cell bank, you could eliminate that and, in principle, have an evergreen supply of starting material.

Regulatory approval pathways could also be streamlined, with the innermost components of an established therapy fine-tuned to meet the needs of specific patients. All these regulatory and manufacturing concepts start to evolve into almost push-button therapeutic manufacturing production methods, producing customized products for end users, adds Vanek. I think thats doable in our lifetime.

The more therapy products that undergo clinical trials and enter the market, the more data will be available to refine treatments and advance therapies further.

This convergence of readily available biological data and our ability to mine big datasets really unlock a lot of potential and value, says Vanek.

Due to the increases in data, uses of artificial intelligence (AI) are widely predicted to increase. Notably, Charles River has been testing out AI in certain processes, having developed a platform called Logica in partnership with Valo Health for drug discovery and design, with several licensing deals announced. The Logica platform has primarily been used for small-molecule development, with other uses across the business being considered.

For preclinical development, and even in a use case like pathology, this could be very useful to help lead developments more efficiently. We have a goal at Charles River to cut up to 12 months off the overall therapeutic development timeline. That wouldnt be in one particular area, it would be across the different parts of therapeutic development, making it more efficient, says Hewitt. There are a lot of use cases we can apply AI to in process and analytical development to ensure that were applying robust standards that give us the best, most stable product process and analytical suite.

The combination of enhanced scientific understanding, growing volumes of data, and advances in manufacturing technologies are all pointing to a future market where the full potential of cell and gene therapy is unlocked across an extensive range of medical treatments for greater numbers of patients.

References:

1. Chen YJ, Abila B, Mostafa Kamel Y. CAR-T: What is next? Cancers (Basel). 2023;15(3):663. doi: 10.3390/cancers15030663.

2. GlobalData. lovances Amtagvi for melanoma treatment grains FDA approval. PharmaceuticalTechnology.com. 19 February 2024. https://www.pharmaceutical-technology.com/news/iovance-amtagvi-melanoma-fda/?cf-view

3. Nelson R. Patients waiting months for Last Chance CAR T-Cell Therapy Medscape.com. 14 July 2022. https://www.medscape.com/viewarticle/977179?form=fpf#vp_1:~:text=The%20team%20contacted,hospice%2C%20or%20died.

AMTAGVI and Iovance are either registered trademarks or trademarks of Iovance Biotherapeutics, Inc. in the United States and/or other countries. Kymriah is either a registered trademark or a trademark of Novartis in the United States and/or other countries. Yescarta is either a registered trademark or a trademark of Kite Pharma, inc. in the United States and/or other countries. Logica and Charles River are either registered trademarks or trademarks of Charles River Laboratories, Inc. in the U.S. and/or other countries. Valo Health is either a registered trademark or a trademark of Valo Health, LLC in the U.S. and/or other countries.

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An alternative to brain surgery for patients with epilepsy – Drug Discovery News

Posted: June 4, 2024 at 2:48 am

The human brain develops through a delicate process where nerve cells grow, move to the right spots, and arrange themselves into functional layers. Abnormalities in this intricate coordination cause malformations in the brain's cortex, leading to focal cortical dysplasia (FCD), the most common cause of epilepsy in children. Patients with FCD are often resistant to anti-epileptic therapy. Surgery to remove the malformed parts of the brain is the standard treatment, which risks altering normal brain function.

In a recent study, researchers at University College London showed that a gene therapy targeted at cortical neurons significantly reduced the frequency of FCD-induced seizures in adult mice (1). It's proof of concept that gene therapy can work after seizures have started, said Angeligue Bordey, a neuroscientist at the Yale School of Medicine who was not involved in the study but who also tested an early treatment to correct seizures before they occurred (2).

Gabriele Lignani led the team that developed a gene therapy to directly address seizures in mice.

credit: Gabriele Lignani

The researchers focused on developing a gene therapy that could directly address seizures, a symptom common to all patients with epilepsy, regardless of cause. By targeting seizure reduction, they aimed to develop a universally applicable treatment. If we decrease the seizures in [FCD] patients, we can have a treatment for all [epilepsy] patients, said Gabriele Lignani, a translational neuroscientist at University College London and study coauthor.

The gene therapy did the job of an antiepileptic drug but was targeted to a specific brain region to mitigate seizures and minimize the side effects typically associated with systemic medications. It's a bit of a different way of doing gene therapy, compared to just correcting a mutation that is really specific for a patient and sometimes more specific to the mouse model than to the patient, Lignani said.

Lignanis research team used an existing mouse model of FCD that involves introducing genetic material into the developing brain of mouse embryos using in utero electroporation. They used a plasmid carrying both a fluorescent marker for easy visualization and a constitutively active Ras homolog enriched in brain (RHEB), an activator of the mechanistic target of rapamycin (mTOR) pathway. Overactivation of mTOR resulted in the characteristic features of FCD, including dysmorphic, enlarged, and misplaced neurons.

To monitor brain activity, the researchers implanted the mice with subcutaneous wireless electrocorticography transmitters positioned over areas showing successful electroporation. This setup allowed for continuous baseline monitoring of brain activity. After 10-15 days of recording, they found that about 65 percent of the electroporated animals exhibited generalized seizures and showed learning disability and impaired social cognition often seen in patients with FCD.

After establishing baseline seizure activity in the mice, the next step was to evaluate the effect of a gene therapy based on overexpression of the Kv1.1 potassium channel, a type of voltage-gated potassium channel that regulates neuronal excitability. Overexpressing Kv1.1 can enhance the outward flow of K+ ions, making neurons less likely to fire excessively, which is a common problem in epilepsy. This channel seems quite good at decreasing excitability and decreasing seizures, Lignani said.

It's a bit of a different way of doing gene therapy compared to just correcting a mutation that is really specific for a patient and sometimes more specific to the mouse model than to the patient. - Gabriele Lignani, University College London

The researchers designed the potassium channel transgene to be most active in the brains main excitatory neurons and packaged it in an adeno-associated viral vector (AAV9). Lignanis team used a cannula to deliver the treatment and monitored brain activity to assess the impact of gene therapy on seizures.

Mice treated with the gene therapy showed a 64 percent reduction in seizures compared to their baselines, with 60 percent of treated animals becoming seizure-free by the end of the observation period. It's a pretty significant reduction, said Bordey. These experiments are very hard to do, so that's an enormous amount of work done.

Lignani believes that this gene therapy could be a viable alternative to surgery for patients with epilepsy. If [gene therapy] works and you don't have seizures, that's it. If it doesn't work, we still have the surgery [to fall back on], he said.

This gene therapy also looks promising for patients with FCD in brain regions where surgery is not an option. Its less invasive, meaning that you need to make a small hole to inject the virus, instead of taking out a big part of the brain, said Lignani.

However, Bordey said that AAV gene therapy comes with its own risks. Once you put it in, it's there for at least five or ten years, she said. If you have a side effect, you're stuck with it.

Lignanis team is gearing up to start a clinical trial in adult patients before expanding to include pediatric cases. This decision is grounded in a comprehensive body of translational preclinical work (3,4). That gives us assurance that we have a good effect, he said. We are quite confident that it works.

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CGT Catapult Joins Forces with CATTI to Create Manufacturing Training Standards for Advanced Therapies – BioPharm International

Posted: June 4, 2024 at 2:48 am

CGT Catapult and CATTI have developed aligned training standards for the manufacture of advanced therapies.

On May 30, 2024, Cell and Gene Therapy Catapult (CGT Catapult) and the Canadian Advanced Therapies Training Institute (CATTI) announced that they developed a strategy that aligns training standards and assessment for the advanced therapies manufacturing industry. The strategy establishes an important first move toward building shared standards to help the advanced therapies manufacturing industry access a skilled workforce, according to a press release.

Advanced therapies are manufactured by highly trained personnel who are good manufacturing practice (GMP)-certified and who know how to operate in aseptic conditions. The current training and assessment for these personnel varies around the world, which makes it difficult for the workforce to relocate and for the industry to access global talent.

This partnership marks a crucial step towards ensuring that our workforce is equipped with the highest level of expertise to meet industry demands. By setting these international standards, we aim to enhance the quality and safety of advanced therapies, ultimately benefiting patients worldwide, said Vanessa Laflamme, CEO of CATTI, in the press release.

CATTI and the CGT Catapult first formed a collaboration in 2023 under which they aim to increase the levels of standardization in the training and assessment standards used in Canada and the United Kingdom. Since then, the organizations have aligned training materials and programs and have outlined a joint strategy that specifies which specific skills and competencies should be assessed. The goal is to establish a rigorous template that can then be applied across all manufacturing training materials and across various skill levels.

By sharing expertise and working with CATTI, a leading provider of training for the advanced therapies industry, we have a valuable opportunity to enhance and standardize the training available to organizations and individuals. This builds on the efforts of the CGT Catapult to date and the investment we have made, alongside government, in developing a successful training program for the UK workforce. Together, we aim to ensure that our growing global sector is supported by a highly skilled workforce equipped with the latest knowledge and skills, said Matthew Durdy, chief executive, CGT Catapult in the release.

CATTI also partnered with bioMrieux Canada in December 2023 to combine their capabilities to enhance workforce training in advanced therapies and the production of quality control solutions for the bio/pharmaceutical industry (1). Under this agreement, bioMrieux is responsible for deploying more than half a million dollars worth of analytical equipment and services in the CATTI training laboratory located at the University of Guelph in Ontario, Canada. The training under this collaboration will equip highly qualified, GMP-certified personnel who are qualified to work under aseptic conditions with the skills and knowledge to manufacture anticancer immunotherapies, cell and gene therapies, vaccines, and other biotherapeutic applications.

1. Canadian Advanced Therapies Training Institute. CATTI and bioMrieux Canada are Joining Forces to Support the Development of a Qualified Workforce in Advanced Therapies. Press Release, Dec. 7, 2023.

Source: CGT Catapult

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CGT Catapult Joins Forces with CATTI to Create Manufacturing Training Standards for Advanced Therapies - BioPharm International

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Gene Therapy is Having its Moment: Can the Clinical Research Ecosystem Seize It? – Contract Pharma

Posted: June 4, 2024 at 2:48 am

Gene therapy research is booming. Since the U.S. Food and Drug Administration (FDA) issued its first approval for a gene therapyin 2017, oncology researchers have been breaking barriers in gene therapy trials, followed by an explosion in mRNA research during the COVID pandemic. Today, this trailblazing science is providing new ways to approach rare diseases and new hope when other investigational interventions have failed. In fact, themajorityof approved gene therapies are for rare diseases 14 are currently in Phase III trials for 10 rare diseases and 45 gene therapies are in early stages of development to treat 30 rare diseases. We see great potential for gene therapies, said Leslie Johnston, senior vice president of biotech delivery for Parexel. As more products are approved, it will gain traction and more companies will look to expand their therapies into other therapeutic indications. This progress presents tremendous potential to change more patients lives across many different diseases. This could be gene therapys moment. But to fully seize it, the industry must clear some complex hurdles. Gene therapies pose several unique challenges for clinical research, including ethical and safety considerations, regulatory hurdles, precarious logistics, and potentially staggering costs. These challenges may already be having ramifications: New U.S. patients treated with gene therapies approved or in development areexpected to fallby one-third from 2025 to 2034. The key to clearing these hurdles? Cooperation between sponsors, sites, regulators, patients, and other stakeholders is essential to expediting the advancement of life-saving gene therapies. Regulators should address risks without limiting innovation Gene therapy trials are strictly regulated and rightly so, due to the novel nature of the intervention and the potential long-term consequences. Gene therapy interventions also carry inherent safety risks, including the potential for unintended genetic changes or adverse immune reactions. Ensuring patient safety requires rigorous monitoring and adherence to strict protocols. However, obtaining regulatory approval under these conditions is time consuming and resource intensive. To avoid hampering scientific progress, regulators should aim to ensure that requirements are appropriately rigorous without being unmanageably onerous. Thankfully, the FDA is paying close attention to gene therapy and has demonstrated a desire to work with drug developers toward the success and approval of these treatments. Dr. Peter Marks, Director of the Center for Biologics Evaluation and Research (CBER) at the FDA, has expressed his hope for an exponential, if not logarithmic, increase in gene therapy approvals. There is a lot of excitement that this could potentially make a big difference for the treatment of human disease, said Dr. Marks in hisremarksto the National Press Forum last November. The FDA is going beyond mere rhapsodizing and taking action to accelerate gene therapy. Last year, the agencylaunched a pilot programcalled Support for Clinical Trials Advancing Rare Disease Therapeutics, or START. This program is designed to accelerate the development and approval process for treatments targeting rare diseases by providing regulatory guidance, assistance, and incentives to sponsors conducting clinical trials in this field. The program represents an important step forward in fostering innovation and collaboration between regulatory bodies and sponsors. In addition, the FDA is working toharmonize global requirementsfor the review of gene therapies. Encouraging and facilitating international cooperation and harmonization of regulatory standards including mutual recognition agreements and shared regulatory pathways for multinational clinical trials can help streamline gene therapy development globally and help bring innovations to patients faster. Even with this progress, regulators should continue to help accelerate gene therapy research by streamlining regulatory pathways specifically tailored to gene therapies. This means providing clear guidance on requirements for preclinical and clinical development, fostering collaboration between stakeholders to share knowledge and best practices, and offering expedited review processes for gene therapy products aimed at treating serious or life-threatening diseases. With a staggering2,500 cell and gene therapyinvestigational new drug applications (INDs) on file, the FDA approved justfivecell and gene therapies in 2023. Dr. Marks hassuggestedthat accelerated approval, which has successfully advanced cancer and HIV/AIDS treatments, may be the most appropriate path for this new category of treatments. But, regulators also need to commit to proactively partner with developers to understand the patient population and the risks and benefits of each new therapy. Likewise, researchers, industry stakeholders, and patient advocacy groups should engage with regulators to help them understand the unique challenges and opportunities in the field of gene therapy. This can help regulators adapt regulatory frameworks to ensure patient safety while expediting the development and approval of promising treatments. Sites and sponsors must be prepared Of course, sites and sponsors also have a crucial part to play in advancing this promising field of medicine. Clinical trial sites should enhance their capacity to conduct gene therapy trials safely and effectively and sponsors should do their part to assist sites in these efforts. By working closely with clinicians and regulators, sponsors can ensure that the trial development process aligns with clinical needs and regulatory standards. Sponsors should have a thorough understanding of FDA requirements pertaining to design, preclinical testing, and long-term follow-up. Better alignment from the outset will lead to more efficient trial designs, faster regulatory approvals, and ultimately quicker patient access to therapies. For example, sponsors working with mRNA and other genetically engineered therapies in North America not only have to go through institutional review board (IRB) review, they also have to navigate additional requirements from the U.S. National Institutes of Health (NIH) Office of Science PolicyGuidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules(NIH Guidelines). These requirements usually involve an additional biosafety risk assessment review from an institutional biosafety committee (IBC) in addition to IRB review. NIH Guidelines apply for any research involving recombinant or synthetic nucleic acids (e.g. genetically engineered materials) that receives NIH support or takes place at sites that have received NIH support for such research. Even when there is zero NIH support, IBC review is considered a best practice. IBC review and inspection helps sites ensure they are fully prepared by identifying areas for improved biosafety protections and calling out gaps in current standard operating procedures (SOPs). Proactive coordination and integration of these separate review processes can speed trial timelines and help sponsors consistently address any potential concerns or issues. Sites can also be better prepared by pre-registering an IBC. The NIH takes six to eight weeks or more to approve a new registration, in addition to IBC review time so by registering an IBC before they even have a trial, sites can save a month or more in startup time over a site that waited to register. Clinical trial sites looking to host gene therapy studies must be prepared in other ways, as well, both in terms of knowledge and infrastructure. Gene therapy studies require specialized infrastructure for manufacturing, storing, and administering genetic material to adhere to strict biosafety guidelines. Something as simple as having an upholstered chair in the infusion room which would pose an unacceptable contamination risk if genetic materials were to spill would require the site to rethink their current processes. Rigorous training is also key due to the added risk of spreading genetic material to caregivers and others in close contact with patients. Research staff must be specially trained to handle, deliver, and dispose of this material safely. Of course, these measures can seem intimidating for sites that are already cost-constrained. Large academic medical centers with more resources and experience are more likely to be well-positioned for these studies. For instance, they may already have conducted bench, animal, and/or agricultural research with genetic engineering or have the funding to make any needed adjustments such as purchasing special equipment. But to maximize the potential number of sites where this research can be conducted and therefore reach more potential participants sponsors might consider providing help in the form of financial assistance, training curricula, SOP guidance, and more to smaller sites seeking to conduct gene therapy research. Logistical complexities depending on the investigational medicine and therapeutic area are among the most complicated challenges in gene therapy trials, added Johnston. From collecting the specimen from the patient, modifying it, storing it, transporting it, and then returning it back to the patient all comes with tremendously unique logistical challenges and requires equally unique equipment, technology, and expertise. And it can be cost-prohibitive. Patients must be fully on board Of course, the most essential stakeholder in any clinical trial is the patient. In gene therapy research, which can be particularly demanding, patients must have a complete understanding of and commitment to their involvement. Understanding the potential risks and benefits can help patients make informed decisions and navigate the study process. First, it's crucial for patients to adhere strictly to the protocol provided by the clinical trial team, including following medication schedules, maintaining specific hygiene practices, and attending all study visits. They should strive to maintain optimal health to enhance the body's response to gene therapy. And to avoid delays, patients should maintain open and honest communication with the clinical trial team, reporting any changes in symptoms, side effects, or general health as soon as they occur. Trial participants also need to be in it for the long haul. Because gene therapy interventions aim to produce lasting effects, even cures, they typically require long-term patient follow-up to assess efficacy and safety. But they may also need to have incredible patience. Johnston explained, There are many complexities that can impact study progress. For example, unpredictable logistical challenges like a weather event or vehicle accident could delay a temperature-sensitive delivery to a site, or data review outcomes could require an indeterminate pause period. Patience and agility are must-haves, but it is difficult for patients potentially depending on this new therapy to save or change their lives. Lastly, the industry cannot forget the patient. Involving patients and patient advocacy groups in the regulatory process can help ensure that the development of gene therapies is aligned with patient needs and priorities, as well as shed light on risk-benefit perspectives from a patients viewpoint. The more these perspectives are considered from the beginning, the greater the chance of a trials success. Rita Naman, co-founder of the Mighty Milo Foundation, emphasizes the need for a more collaborative and patient-centered approach to gene therapy development. "For ultra-rare diseases likeSPAX5, gene therapy offers a glimmer of hope where traditional treatments do not. But logistical hurdles make these therapies expensive and inaccessible, explained Naman. Closer collaboration with patients, industry, and regulators could streamline these processes, drive costs down, and speed trials. Patients like my son, and their caregivers, plus advocacy groups should be invited into the earliest discussions to prevent false starts or missed milestones in gene therapy development especially as the patients priorities dont always line up with the sponsors. In the fight for gene therapy breakthroughs, cooperation is key. The road to operationalizing gene therapy clinical trials is laced with land mines and potholes. To capture the full potential of novel gene therapy research, a new level of collaboration between sponsors, CROs, sites, oversight committees, regulatory bodies, and patients is paramount. Patients want access to novel gene treatments, and they want it fast. Sponsors want to deliver but fight logistical and financial obstacles. Regulators want to ensure safety first, especially considering such new, promising science, concluded Johnston. These three goals may seem conflicting at times, so we need to strike a balance of safety and speed, so patients dont miss their only potential treatment opportunity. A seasoned industry veteran with more than 25 years of experience, James Riddle is senior vice president of global review operations at Advarra. Riddles expertise includes large program management and growth, operational processes, development and implementation of technology solutions, and management of large Human Research Protection Programs (HRPP), Biosafety programs (IBC) and Institutional Animal Care and Use programs (IACUC). Riddle has directed numerous clients in achieving Part 11 compliance and meeting computer system validation requirements.

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