Category Archives: Genetic Therapy

CAR-T therapies have revolutionised the treatment of some blood cancers, but are costly as well as time- and resource-intensive. Now, US researchers think one solution could be an implant that generates T cells within the body to attack the cancer.

It is early days for the concept, but its developers from North Carolina State University and the University of North Carolina have completed a proof-of-concept study that shows it works in animal models and could start to attack the cancer in a single day.

At the moment, it can take weeks to complete the CAR-T process, which includes harvesting of T cells from the patient an shipment to a manufacturing unit, engineering, activation, and expansion of the cells, quality control checks and shipment back to the hospital for re-infusion into the patient.

In some cases where the cancer is particularly aggressive, that timeframe may simply be too long to be a viable option for the patient. It is also expensive, at up to $500,000 per procedure.

The UNC and NCSU team, led by biomedical engineer Yevgeny Brudno, report in Nature Biotechnology how they have developed an implant that can generate the CAR-T cells in vivo.

It is based on an FDA-approved biocompatible, sponge-like material called MASTER, which has antibodies that activate T cells as well as interleukins that promote proliferation.

A mixture of T cells isolated from the human donor and viral particles to engineer them is introduced into the sponge, which is then surgically implanted into the patient the same day. The T cells are modified, activated and proliferate all within the implant from which they are steadily released as fully functional CAR-T cells to attack the tumour.

In a mouse model carrying human lymphoma cells, the CAR-T cells made in the implants were better at fighting the cancer cells than a control group manufactured using the current production method and delivered intravenously.

They were also healthier, with superior sustainability in the body and more anticancer potency, and showed fewer signs of differentiation or other cellular changes associated with T-cell exhaustion, a condition in which they lose activity.

The CAR-T cells targeted CD19, working in a similar way to current commercial CAR-Ts from Gilead Sciences, Novartis and Bristol-Myers Squibb.

Our MASTER technology takes the cumbersome and time-consuming activation, reprogramming and expansion steps and performs them inside the patient, said Dr Pritha Agarwalla, one of the researchers behind the work.

The large pores and sponge-like nature of the MASTER material brings the virus and cells close together, which facilitates cellular genetic reprogramming, she added.

The researchers also found that the improvement in anticancer efficacy was particularly noticeable over the long term, when mice were reimplanted with lymphoma cells to represent a recurrence.

They now want to test the implant approach to see how it performs against solid tumours, which have proved to be a challenging target for current CAR-T therapies.

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Implants could transform CAR-T therapy into one-day procedure - - pharmaphorum

Compared to a critical organ that had been largely ignored, companies working to develop microbiome-based therapies believe there is untapped potential in the area. Ben Hargreaves speaks to companies that are developing therapies not just in gastrointestinal conditions but also in broader areas, such an immuno-oncology.

The interest in how the human microbiome influences health has grown substantially in the last decade. PubMed cites 1,822 pieces of research relating to the microbiome in 2011, which grew to 25,153 published in 2021. As more research has been conducted, closer and unexpected links have been found between the microbiome of the gut, as one example, and other areas of the body, such as brain health and the immune system.

The microbiome, as a term, can be related to the nasal, oral, skin, gastro-intestinal, and urogenital regions of the human body, each containing varied microbial communities that have an impact on health. Research into the area is being made possible through advancements in technology, such as being able to sequence genes at scale, allowing researchers to gain more detailed genetic data on the microbiome.

With more research being published, there has arrived greater interest in how individual microbiomes could influence health and there is now a growing market of prebiotic, probiotic and postbiotic commercial products based on the links being made to various health conditions. At the same time, the pharma industry has also started to note the potential for a new treatment paradigm to be developed, and investment into the space has started to increase. As a result, pharma companies such as Merck, Gilead, Genentech, Johnson & Johnson and Takeda have positioned themselves alongside partners to benefit from a potential new wave of treatments.

More recent research has also suggested that there are links to the health of the heart and to the brain, through an impact on mental health.

The possibilities

The gut contains approximately one trillion microbes and at least 160 bacterial species that are constantly interacting with one another and with the cell lining of the gut. The gut microbiome has long been linked to gastrointestinal conditions, such as inflammatory bowel disease and irritable bowel diseases, as well as obesity and type 2 diabetes. More recent research has also suggested that there are links to the health of the heart and to the brain, through an impact on mental health, with the latter becoming so established as to become known as the gut-brain axis.

Due to the variety of potential indications that can be targeted in ensuring a healthy gut, the work being carried out by pharma and biotech companies in the space is often concentrated in this area. Seres Therapeutics is a biotech that has specialised in the microbiome space and also possesses one of the assets closest to potential approval in the overall pipeline. Its treatment candidate, known as SER-109, is targeting patients with recurrent C. difficile infection (CDI).

The treatment has been granted US FDA breakthrough therapy designation and orphan drug designation, and has also completed a phase 3 clinical study. In the trial, Seres announced that the product candidate had met its primary endpoint, showing a statistically significant 30.2% absolute reduction in the rate of CDI recurrence compared to placebo. As a result, the treatment candidate is the most advanced one in the overall microbiome pipeline, with an approval holding the potential to advance the entire field, as well as Seres own prospects. Speaking to pharmaphorum, the companys CEO, Eric Shaff, said, Our investigational SER-109 has clearly validated our approach, and there is tremendous opportunity to apply our microbiome therapeutics more broadly to infection protection across multiple patient populations and disease areas.

Mid-way through last year, Nestl confirmed its conviction in the project by consolidating its existing partnership with Seres through paying $175 million upfront for North American co-marketing rights to the potential microbiome therapy. The biotech is eligible to receive a further $125 million if the FDA approves the drug and could receive another $225 million in commercial milestones. If approved by the FDA, the treatment would become the first microbiome-based treatment to receive approval.

In regard to future work, Shaff stated, Given what weve learned from our lead investigational program, SER-109, were especially focused on how to use microbiome therapeutics to provide infection protection to medically compromised patients.

Eyes bigger than the belly

Even though many microbiome-based therapies are looking to gastrointestinal conditions, the rest of the pipeline is much broader. Finch Therapeutics, which is partnered with Takeda on several drug candidates, is developing FIN-211 for autism spectrum disorder (ASD). The company states that a subset of individuals with the condition also exhibit the most common gastrointestinal (GI) disorders, with the expectation that treatment could address both the GI and behavioural symptoms by targeting multiple ASD-relevant pathways.

4D Pharma, another biotech working in the space, has a pipeline of products that predominantly target either immuno-oncology or central system disorders indications. There is now a growing body of research to suggest that the microbiome of a patient can impact responses to immunotherapy. The potential was enough for both Pfizer and Merck to decide to collaborate with 4D to test combination treatments of their immunotherapies, Bavencio (avelumab) and Keytruda (pembrolizumab), respectively. Both treatments will be tested alongside MRx0518, which is also being tested as a monotherapy, after 4D found that the microbiome therapy was able to increase key immune biomarkers associated with anti-cancer immune response and responses to therapy and was associated with better clinical outcomes in early trials.

Compelling advantages

A spokesperson for 4D Pharma explained to pharmaphorum that microbiome-based therapies, or Live Biotherapeutic Products (LBPs) as they are also known, are attractive to use in combination due to their safety profile.

As naturally occurring non-engineered strains of human commensal bacteria originally isolated from healthy human donors, they are expected to have very clean safety profiles, they said. This also means LBPs are attractive as combination therapies, driving better efficacy without additional toxicity concerns.

Beyond this, the spokesperson added that LBPs could go beyond what is therapeutically possible with traditional small molecules or biologics. This is due to their ability to hit multiple targets with the same drug, which, alongside the expected safety profile of the treatments, could offer advantages over existing treatments.

More broadly, the microbiome can be thought of as analogous to a critical organ that we previously overlooked or underappreciated, but is involved in the proper functioning of a wide range of human systems from metabolism to immunology (including immuno-oncology) and neurology via the gut-brain axis. By understanding these impacts, the microbiome offers a whole new way to think about treating many different diseases, the spokesperson concluded.

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Understanding the microbiome as an 'overlooked critical organ' - - pharmaphorum

By Reka Geczy, PhD, Aruna Balgi, Stella Park, Rita Zhao, Ethan Watt, Maggie Wong, Cooper Webb, Nikita Jain, PhD, Angela Zhang, PhD, Anitha Thomas, PhD, Samuel Clarke, PhD

The expression of the chimeric antigen receptor (CAR) on T cells turns a patients cells into cell-based cancer therapies and has revolutionized cancer treatment today1. Despite its successes and high response rates, evidence suggests an increasing need for more complex genetic engineering enabled by CRISPR/Cas-mediated genome editing technologies. Such examples include the disruption of inhibitory pathways exploited by the tumor microenvironment2, 3, improvement of CAR T cell efficiency4, 5, and manufacturing of universal CAR T cells from allogeneic donors6, 7. The desire to achieve both gene editing and transgene expression in next-generation T cell therapies emphasizes the significance of the genetic material delivery method, which plays a critical role in cell function, cell yield, ease of production, and scale-up.

A promising new approach for T cell engineering is the use of RNA to express therapeutic proteins and gene editing nucleases. RNA is typically delivered to cells using electroporation; however, the sequential electrical pulses for multi-step gene engineering leads to a dramatic trade-off between efficiency and cell viability. This type of trade-off is not observed with lipid nanoparticles (LNPs), making it an attractive alternative for RNA delivery. LNPs are entirely synthetic lipid formulations designed to encapsulate and protect RNA before delivering it into cells. The production of LNPs is well-established and is scalable for large-scale gene delivery and gene editing, which are key to meeting clinical demand now and in the future. The RNA-LNP complex structurally resembles low density lipoproteins (LDL) and can co-opt the endogenous uptake pathway of LDL to enter cells using receptor-mediated endocytosis. This gentle uptake mechanism enables successful genome engineering of T cells while maintaining high cell viability.

Herein, we report a novel method for sequential genetic engineering of T cells using the GenVoy-ILM T Cell Kit for mRNA. We utilized a manufacturing workflow optimized to deliver various RNA cargoes. In this case study, we show CRISPR/Cas9-mediated knockouts (KO) of the T cell receptor (TCR) and explore multi-step LNP engineering to produce TCR KO CAR T cells, a promising approach towards allogeneic CAR T cell therapy6, 8, 9. We describe in detail LNP production and cell culture treatment protocols, as well as optimization strategies for T cell gene editing to ensure success with the GenVoy-ILM T Cell Kit for mRNA.

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Genome Editing of Human Primary T Cells With Lipid Nanoparticles - BioProcess Online

Shares of Taysha Gene Therapies are down more than 10% after apatient'sdeath marred positive interim data for the companys experimental gene therapy treatment for Sandhoff and Tay-Sachs diseases, which are two forms of GM2 gangliosidosis.

The first patient treated with Texas-based Tayshas TSHA-101 was diagnosed with Sandhoff disease, arare inherited disorder that progressively destroys brain and spinal cord nerve cells. After administering TSHA-101, an investigational gene therapy that delivers both the HEXA and HEXB genes that make up the -hexosaminidase A enzyme, the patient demonstrated clinical improvement after three months. The patient was cleared to travel home. However, Taysha said the unvaccinated patient was exposed to a family member who was symptomatic of an upper respiratory infection, which was likely COVID-19. The Taysha patient was hospitalized with pneumonia. While there, the patient contracted a secondary hospital-acquired methicillin-resistant staphylococcus aureus (MRSA) infection and ultimately succumbed.

Trial investigators have made the initial assessment that the patients death was not likely due to the gene therapy. However, according to the company, a review from the independent data safety monitoring board is being conducted and results are anticipated in the near term.

Prior to the patients death, Taysha said their disease had realized normalization of Hex A enzyme activity by the end of the first month following treatment with the gene therapy. The levels were 58-fold above the presumed asymptomatic level of 5% of normal identified by natural history at Month 3, the company said. According to available data, the patient achieves Hex A enzyme activity of 190% and 288% of normal at month 1 and month 3, respectively.

The second patient to receive the gene therapy is a Tay-Sachs patient. Another rare genetic disorder, Tay-Sachs is caused by the absence of an enzyme that helps break down fatty substances known as gangliosides. Without the ability to break them down, gangliosides build up to toxic levels in the brain and spinal cord, leading to early death.

After dosing with TSHA-101, the Tay-Sachs patient achieved Hex A enzyme activity of 25% of normal at month 1. That data represents a 5-fold improvement above the presumed asymptomatic level of 5% of normal identified by natural history.

Despite the early death that is possibly related to COVID-19, Taysha said the data for TSHA-101 is the first-ever to support the bicistronic vector approach in humans delivering bothHEXAandHEXBgenes in the endogenous ratio. Although the cause of the patients death is still under review, the company said preliminary data suggest that TSHA-101 was well-tolerated with no significant drug-related events.

TSHA-101 is the only bicistronic vector currently in clinical development for GM2 gangliosidosis and has been granted Orphan Drug and Rare Pediatric Disease designations by the U.S. Food and Drug Administration. It has also been granted Orphan Drug designation from the European Commission.

TSHA-101 is the first bicistronic vector in clinical development, representing an important first for the field of gene therapy, RA Session II, president, founder and chief executive officer of Taysha, said in a statement. TSHA-101 demonstrated expression of bothHEXAandHEXBgenes in the endogenous ratio, providing the ability to restore and normalize enzyme activity in GM2 gangliosidosis. We expect to provide continued updates on the program, with additional clinical data anticipated by the end of 2022.

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Taysha's Promising Gene Therapy Results Marred by Patient's Death - BioSpace

Homology Medicines has found a source of fresh funding. With its share price in the doldrums and its cash runway nearing its final year, Homology is offloading manufacturing assets through a joint venture to raise $130 million for clinical development of gene therapies.

The deal will see Homology and U.K.-based lentiviral specialist Oxford Biomedica create a joint venture focused on adeno-associated virus (AAV) vectors. Homology is contributing its AAV process development and manufacturing platform, intellectual property, Boston plant and employees including Chief Operating Officer Tim Kelly. Oxford Biomedica is paying $130 million for an 80% stake in the new company.

The $130 million cash infusion, coupled with the reduction in operating expenses, significantly extends our runway and supports the continued advancement of our programs and genetic medicines platform, Homology CEO Arthur Tzianabos, Ph.D., said in a statement.

Homology ended September with $187.6 million. Based on its projected burn rate, Homology calculated the money would fund its operations into the first quarter of 2023. Homologys ability to raise money on public markets is limited by its share price, which has fallen 76% over the past year to below $4. Novartis walked away from a collaboration with Homology around 11 months ago.

RELATED: Pfizer invests $120M in 4 biotechs through new growth fund

Phase 2 data on Homologys lead gene therapy in adult phenylketonuria are due around the middle of the year, meaning the biotech would have had a chance to improve its share price before reaching the end of its cash runway. But with the Oxford Biomedica deal Homology has found a way to raise cash and extend its runway without offering stock.

The deal will leave Homology reliant on the joint venture, Oxford Biomedica Solutions, for manufacturing services. Homology, which will own 20% of the venture, has a multi-year supply agreement as a preferred customer with minimum contracted revenue of approximately $25 million for the first year.

After the three-year anniversary of the closing of the deal, either party can trigger the sale of Homologys 20% stake. The deal values the stake at 5.5 times Oxford Biomedica Solutions revenue for the previous 12 months. The most Homology can receive for the stake is $74.1 million.

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Homology scratches cash itch with manufacturing deal, bagging $130M to fund gene therapy trials - FierceBiotech

Gene therapies have yielded promising results for individuals experiencing rare diseases. However, these groundbreaking therapies come with their own unique set of challenges regarding who will be able to access them, how much they will cost, and how the policymaking and scientific processes will conflict as more and more therapies undergo clinical trials.

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Last week, we convened a panel of experts to address these questions and discuss potential solutions in our latest 5 Slides Were Watching conversation, led by State of Reforms DJ Wilson. The panel featured Danny Seiden, president & CEO of the Arizona Chamber of Commerce and Industry, Dr. Jennifer Hodge, U.S. DMD Gene Therapy Lead at Pfizer, Dr. Rafael Fonseca, chief innovation officer at Mayo Clinic, and Dr. Sharon Hesterlee, chief research officer at the Muscular Dystrophy Association.

Hesterlee brought a slide showing the prevalence of rare diseases in Arizona, noting that 5,500 Arizonans were estimated to be living with rare genetic neuromuscular diseases that were potentially treatable with gene therapy. She highlighted that Charcot-Marie-Tooth disease and Myotonic dystrophy were the most prominent, and that both diseases currently have gene therapy treatments in preclinical development.

She emphasized that ethics need to be an important part of the conversation, and that it will be critical to educate patients and families about the treatments irreversible implications as more and more therapies begin to launch.

Its a permanent change to someone. What we see in particular with parents of a child who has a pediatric disease, they are put in a very difficult position because they have to make a decision without always understanding all of the science and all of the implications.

So I think there is a huge requirement for the physician [who does the informed consent] to be very clear, and then the parents have to decide if it doesnt work, my child cannot be redosed, my child may not be eligible for another trial I think thats been a big challenge and something that weve tried to help our community in the neuro-muscular disease space navigate.

Seiden brought a slide displaying the economic benefits that would come with the increased prevalence of gene therapies. He noted that outdated systems of payment would not be applicable to this kind of treatment, and that these therapies would allow for one-time costs as opposed to a lifetime of treatment for patients with rare diseases.

When you deal with rare diseases, you need to look at it on an annualized basis over the cost of a lifetime, because gene therapy has the potential to save money and a lot of heartache for the patients and the families involved with it Arizona is one of a handful of states that allows for value-based purchasing when it comes to Medicaid contracts With the [Arizona Health Care Cost Containment System (AHCCCS)], which is by far the largest provider, theyve recognized that you have to look at patient outcomes. Its not just about that initial upfront cost.

Hodge presented a slide illustrating the unmet needs of individuals with rare diseases and the potential impacts that gene therapies can have on these individuals. She emphasized the urgent need for innovative treatments for these diseases, as 95% of rare diseases worldwide have limited or no approved treatment options, and 80% of those rare diseases have a genetic cause. She said this makes patients with rare disease collectively one of the most underserved communities in medicine today.

She said educating every organization involved in the process of developing these therapies on the stories of real patients affected by these diseases will be critical as gene therapies move through both scientific and legislative processes.

Its really to address the underlying cause of rare diseases at the root, meaning the genetics, not the symptoms It cant be a line item in a bill, it cant be something on a piece of paper that you hear about, it has to be someone telling their story [and] thinking about the patient and what theyre going through.

You can learn so much by just sitting and talking and just hearing their story, and little things that you didnt even know affected them We need to bring that to more of the audience thats involved in making some of these decisions so they can see it as more than just a line on a piece of paper when theyre deciding something.

Fonseca showed a slide explaining some specific uses of gene therapy that could potentially provide individualized, life-saving treatment to people with red blood cell diseases, as well as preventive genetic interventions for diseases like cancer.

When you think about this approach in looking at the rare disorders, it turns out that by extrapolation, a lot of the diseases that we consider common also become more and more individualized, and therefore, theyre more and more unique. More and more, we see approaches that have to be very, very much [a] tailored design for patients

To have someone who is born with [a red-blood cell disorder] return to normal red blood cell function is just enormous. This is a worldwide problem, its a problem thats associated with pain, serious medical problems, a shorter lifespan, and great expenditures for the health system, and so [Im very excited about where were at with this].

Wilson highlighted that while few gene therapies have been officially launched in the market, many are currently in pre-clinical and clinical trials and are expected to provide promising health solutions for the future.

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5 Slides We're Discussing: Gene therapy and the promise for rare disease - State of Reform - State of Reform