Category Archives: Transhuman News

New York, NY (October 17, 2022) Researchers at Mount Sinais Tisch Cancer Institute have identified a new gene that is essential to colon cancer growth and found that inflammation in the external environment around the tumor can contribute to the growth of tumor cells. The scientists reported these findings in Nature Communications in October.

This is the first time that scientists have discovered that the environment around a colon cancer tumor can program what is known as a super enhancer, a complex area of DNA with a high concentration of transcriptional machinery that controls whether a cell is malignant.

This super enhancer --the largest 1-2% of all enhancers in the cell -- regulates the gene PDZK1IP1, which was previously not identified as a cancer gene. Once researchers deleted PDZK1IP1, colon cancer growth slowed down, suggesting that PDZK1IP1 and its super enhancer could be targets for anti-cancer therapies.

In the United States, colon cancer is the third most prevalent and second most deadly cancer, said the studys first author Royce Zhou, an MD/PhD student at the Icahn School of Medicine at Mount Sinai. This cancer is reliant on surgery for treatment, and immunotherapies that have revolutionized the treatment of advanced cancer have only worked for a small subset of colon cancer patients. Thats why theres a great need for novel target identification.

This study found that the super enhancer is activated by surrounding inflammation in the tumor microenvironment. The inflammation allows the cancer cells to survive in an environment they otherwise would not. Inflammatory bowel disease is a known risk for colon cancer; this finding could add to the understanding of the mechanism involved.

What this means for most patients with colon cancer is that inflammation thats occurring in the tumor is contributing to the tumors growth. This stresses the importance of understanding what we can do to curb the inflammatory effects in the colon through prevention or understanding what dietary effects might have on the microenvironment in the colon, said senior author Ramon Parsons, MD, PhD, Director of The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. In terms of treatment, we have genetic evidence that targeting this gene actually inhibits tumors. By understanding all these different components, we will have better tools to try to prevent the disease.

This discovery was made possible by studying live tumor tissue and surrounding healthy tissue immediately after the surgeries of 15 colon cancer patients. Being able to prepare and analyze live cells allowed researchers to see the tumor microenvironment and the genetic and biologic drivers of colon cancer, Mr. Zhou said.

We had live specimen live cells straight from the operating room that allowed us to immediately measure the epigenetic state of that tumor, Dr. Parsons added. Without that infrastructure here at Mount Sinai, we couldnt have made this discovery.

About the Mount Sinai Health System

Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.

Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked byU.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology.U.S. News & World ReportsBest Childrens Hospitals ranks Mount Sinai Kravis Children's Hospital among the countrys best in several pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 byU.S. News & World Report's"Best Medical Schools," aligned with aU.S. News & World Report"Honor Roll" Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas.NewsweeksThe Worlds Best Smart Hospitals ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.

For more information, visithttps://www.mountsinai.orgor find Mount Sinai onFacebook,TwitterandYouTube.

Nature Communications

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Study identifies new gene that drives colon cancer - EurekAlert

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Updated Stroke Gene Panels: Rapid evolution of knowledge on monogenic causes of stroke | European Journal of Human Genetics - Nature.com

CRISPR-Cas9 is revolutionizing all facets of drug discovery, allowing for both a deeper understanding of disease processes, and for the development of ground-breaking genetic medicines.

As these new classes of cell and gene therapies translate to the clinical setting, some key bottlenecks remain to be solved before the technology will realize its full societal impact.

Dr Alasdair Russell, CSO of Zygosity, highlights where the field is at with some of the most talked about bottlenecks, namely those involving the safety of CRISPR technologies.

CRISPR-Cas9 is an incredibly precise and efficient tool, however it can be prone to rare, unintended editing away from the target gene. While it is true that CRISPR can edit at unintended sites of the genome, raising valid safety concerns, there are now a swathe of computational tools and assays available to assess and quantify these events.

Indeed, in March this year the FDA released draft guidance on the use of CRISPR in gene therapy products. The FDA recommends characterization of on- and off-target editing using multiple orthogonal methods (e.g. in silico, biochemical or cell-based assays) and across multiple patient samples (where possible).

With this framework in mind, leading CRISPR therapy companies have published their off-target strategies in an effort to align the field in a spirit of openness, giving a clear roadmap for future CRISPR therapy development.

CRISPR-Cas9 works by cutting DNA within a gene and allowing error-prone DNA repair to introduce errors in the hope that these will silence the target gene. DNA repair in the cell is probabilistic, in that a given DNA cut can be repaired in any number of different ways.

What this looks like when applied to a group of cells (e.g. T-cells for a CAR-T therapy) or an intact tissue (e.g. retinal tissue in the eye) is that different cells will contain different edits and not all of them will silence the target gene. This is a type of genetic impurity (called mosaicism) and is pervasive across all species.

Currently there are no viable solutions to solve genetic impurity at the target site for cell and gene therapy.

Other, less common, but still undesirable events affecting the target gene include large deletions and genomic rearrangements. Several academic groups have observed rare loss of long stretches of DNA at the target site after prolonged exposure to CRISPR-Cas9. Further, when multiple genes are targeted for silencing simultaneously, it is possible for intervening segments of the genome to shuffle.

This phenomenon, at least in part, has contributed to Beam Therapeutics FDA hold on the BEAM-201 base editor. In response to this hold, the field has adopted a more rigorous approach to mapping the frequency of any genome shuffling in a manner akin to how off-target editing is now being approached. Indeed, the draft guidance by the FDA recommends an assessment of genome shuffling and large deletions by robust methodologies.

The overwhelming majority of CRISPR therapy companies have at least one program focused on next generation cell therapies. To enhance these therapies (persistence, efficacy, safety) multiple genes need to be silenced within a given cell. Multiplex silencing represents a significant roadblock to CRISPR realizing its full potential in this space.

It is now recognized that between three and 12 gene modifications are necessary to enhance autologous and allogeneic CAR-T therapies respectively. As described above, CRISPR results in genetic impurity at the target gene, with only a fraction of edits silencing the gene. Importantly, as you scale the number of genes to be silenced, you drastically reduce the probability that you will get a cell that contains all the desired edits in it.

As an exemplar, there are published cases where triple-gene silenced next generation CAR-T therapies administered to patients contained less than 2% of cells with the desired edit across all three genes. The low proportion of multiplexed edited cells presents an enormous manufacturing challenge as investigators have to invest heavily in novel methods to purify out these rare, therapeutically relevant cells.

In some settings this presents an enormous hurdle, for example autologous cell therapies where the patient-derived T-cells themselves which are used to make the CAR-T medicine are compromised. This is due to the T-cells being derived from patients who have received a toxic preconditioning chemotherapy regimen. In this setting, multiplex gene editing to generate next generation CAR-T medicines is generally considered infeasible.

To get around this issue, the majority of CAR-T programs focus on using healthy donor T-cells as a base upon which to develop off-the-shelf CAR-T medicines. Here the challenge is that often substantially more genes (up to 8-12) may need to be silenced to overcome rejection due to the CAR-Ts being seen as foreign (graft vs host disease).

This presents the concept of the multiplex editing ceiling, above which it is unfeasible to silence more genes (due to genetic impurity). Currently the multiplex ceiling falls significantly short of the 8-12 genes needed to be silenced simultaneously. This multiplex ceiling driven by DNA impurity at the cut site will need to be overcome if the next generation CAR-Ts are going to help the market expand from $1.2 billion (2021) to $22 billion in 2031 as predicted.

Looking forward, as we move to treat more and more genetic disease within the body, we will need to grapple with genetic impurity. Within an intact diseased organ it is impossible to apply a manufacturing process to purify out cells with desirable edits. Until this is solved, only diseases with broad therapeutic windows (i.e. small levels of gene correction or silencing) will be accessible to most CRISPR technology.

Further, a less appreciated bottleneck is the fact that the vast majority of cells in our bodies which are affected by genetic disease are not undergoing active cell division. This is an important observation as all current technologies for rewriting genes (including base editors and PRIME editors) are inefficient in cells that are not cycling. We as a field will have to reconcile this if CRISPR is truly to revolutionize medicine.

Zygosity is a proprietary genome editing platform that develops accurate and precise CRISPR medicines that are not burdened by impure edits and unpredictable phenotypes.

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The challenges of translating CRISPR to the clinic - Labiotech.eu

Studies in non-human primates demonstrated nearly 100% gene editing and knockout of endogenous RHO gene and more than 30% replacement protein levels using a dual vector AAV approach

Treated eyes showed morphological and functional photoreceptor preservation

EDIT-103 advancing towards IND-enabling studies

CAMBRIDGE, Mass., Oct. 13, 2022 (GLOBE NEWSWIRE) -- Editas Medicine, Inc. (Nasdaq: EDIT), a leading genome editing company, today announced ex vivo and in vivo preclinical data supporting its experimental medicine EDIT-103 for the treatment of rhodopsin-associated autosomal dominant retinitis pigmentosa (RHO-adRP). The Company reported these data in an oral presentation today at the European Society of Gene and Cell Therapy 29th Annual Meeting in Edinburgh, Scotland, UK.

EDIT-103 is a mutation-independent CRISPR/Cas9-based, dual AAV5 vectors knockout and replace (KO&R) therapy to treat RHO-adRP. This approach has the potential to treat any of over 150 dominant gain-of-function rhodopsin mutations that cause RHO-adRP with a one-time subretinal administration.

These promising preclinical data demonstrate the potential of EDIT-103 to efficiently remove the defective RHO gene responsible for RHO-adRP while replacing it with an RHO gene capable of producing sufficient levels of RHO to preserve photoreceptor structure and functions. The program is progressing towards the clinic, said Mark S. Shearman, Ph.D., Executive Vice President and Chief Scientific Officer, Editas Medicine. EDIT-103 uses a dual AAV gene editing approach, and also provides initial proof of concept for the treatment of other autosomal dominant disease indications where a gain of negative function needs to be corrected.

Key findings include:

Full details of the Editas Medicine presentations can be accessed in the Posters & Presentations section on the Companys website.

About EDIT-103EDIT-103 is a CRISPR/Cas9-based experimental medicine in preclinical development for the treatment of rhodopsin-associated autosomal dominant retinitis pigmentosa (RHO-adRP), a progressive form of retinal degeneration. EDIT-103 is administered via subretinal injection and uses two adeno-associated virus (AAV) vectors to knockout and replace mutations in the rhodopsin gene to preserve photoreceptor function. This approach can potentially address more than 150 gene mutations that cause RHO-adRP.

AboutEditas MedicineAs a leading genome editing company, Editas Medicine is focused on translating the power and potential of the CRISPR/Cas9 and CRISPR/Cas12a genome editing systems into a robust pipeline of treatments for people living with serious diseases around the world. Editas Medicine aims to discover, develop, manufacture, and commercialize transformative, durable, precision genomic medicines for a broad class of diseases. Editas Medicine is the exclusive licensee of Harvard and Broad Institutes Cas9 patent estates and Broad Institutes Cas12a patent estate for human medicines. For the latest information and scientific presentations, please visit http://www.editasmedicine.com.

Forward-Looking StatementsThis press release contains forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "target," "should," "would," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The Company may not actually achieve the plans, intentions, or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in the initiation and completion of preclinical studies and clinical trials and clinical development of the Companys product candidates; availability and timing of results from preclinical studies and clinical trials; whether interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials or to market products and availability of funding sufficient for the Companys foreseeable and unforeseeable operating expenses and capital expenditure requirements. These and other risks are described in greater detail under the caption Risk Factors included in the Companys most recent Annual Report on Form 10-K, which is on file with theSecurities and Exchange Commission, as updated by the Companys subsequent filings with theSecurities and Exchange Commission, and in other filings that the Company may make with theSecurities and Exchange Commissionin the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and the Company expressly disclaims any obligation to update any forward-looking statements, whether because of new information, future events or otherwise.

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Editas Medicine Presents Preclinical Data on EDIT-103 for Rhodopsin-associated Autosomal Dominant Retinitis Pigmentosa at the European Society of Gene...

Until recently, researchers could not see gene expression in an individual cell. Thanks to single cell sequencing techniques, they now can. But the timing of changes is still hard to visualize, as measuring the cell destroys it.

To address this, we developed an approach based on models in basic physics, explained Welch, treating the cells like they are masses moving through space and we are trying to estimate their velocity.

The model, dubbed MultiVelo, predicts the direction and speed of the molecular changes the cells are undergoing.

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Our model can tell us which things are changing firstepigenome or gene expression--and how long it takes for the first to ramp up the second, said Welch.

They were able to verify the method using four types of stem cells from the brain, blood and skin, and identified two ways in which the epigenome and transcriptome can be out of sync. The technique provides an additional, and critical, layer of insight to so called cellular atlases, which are being developed using single cell sequencing to visualize the various cell types and gene expression in different body systems.

By understanding the timing, Welch noted, researchers are closer to steering the development of stem cells for use as therapeutics.

One of the big problems in the field is the artificially differentiated cells created in the lab never quite make it to full replicas of their real-life counterparts, said Welch. I think the biggest potential for this model is better understanding what are the epigenetic barriers to fully converting the cells into whatever target you want them to be.

Additional authors on this paper include Chen Li, Maria C. Virgilio, and Kathleen L. Collins.

Paper cited: Single-cell multi-omic velocity infers dynamic and decoupled gene regulation, Nature Biotechnology. DOI: 10.1038/s41587-022-01476-y

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Mathematical model could bring us closer to effective stem cell therapies - Michigan Medicine

As a top regulator at the Food and Drug Administration, Peter Marks isnt responsible for weighing the cost of the treatments his teams review. But he is worried that some of the drug industrys most promising medicines may not reach patients with uncommon diseases if companies cant figure out how to sell them.

There are an estimated 7,000 rare diseases, many of which affect only small groups of people. Genetic medicines, including RNA-based drugs and gene replacement therapies, could offer a powerful way to treat, and potentially even cure, some of them. But for would-be developers, diseases affecting only a few dozen people might not represent a large enough market to justify the cost of developing and selling a new treatment.

We're not going to find enough philanthropic groups to foot the bill for gene therapies for the hundreds upon hundreds of different diseases that need to be addressed, said Marks, head of the FDAs Center for Biologics Evaluation and Research, at a conference hosted by the Alliance for Regenerative Medicine on Wednesday.

We're gonna have to find a way to make this commercially viable so that industry can find a way forward towards this."

According to Marks, commercial viability for a gene therapy means administering roughly 100 to 200 treatments a year, a threshold that could be difficult to clear in a single country for rare conditions like severe combined immunodeficiences or adrenoleukodystrophies.

It has not escaped our attention at FDA that there have been some clouds on the horizon in gene therapy, said Marks, noting instances when gene therapies were taken off the market or returned by their developers to the original academic researchers.

In Europe, for example, first GSK and then Orchard Therapeutics abandoned one of the first gene therapies approved there, a treatment called Strimvelis for a condition known as ADA-SCID. Only a few dozen patients were ever treated, and Orchard has also handed back rights to a successor treatment. More recently, Bluebird bio withdrew two gene therapiesfrom the EU market after running into difficulties securing reimbursement in several European countries.

Bluebird recently won FDA approval for both of those therapies in the U.S. One, to be sold as Skysona at a cost of $3 million, is for an inherited condition known as CALD that affects about 50 boys each year. Bluebird has said it expects to treat around 10 each year.

In his remarks to the conference, known as the Meeting on the Mesa and attended by many in the cell and gene therapy field, Marks highlighted a few areas where the FDA could help ease hurdles for ultra-rare disease treatments.

The agency is currently putting together a cookbook for developing and manufacturing of bespoke gene therapies, which could help academic groups more easily transfer treatments theyre working on to industry. Its also looking into how to use non-clinical and manufacturing data from one application to speed the review of others that share similar technology.

There are certain pieces of gene therapies that are not like your typical small molecule drug, because they're reused repeatedly, Marks said.

Automated manufacturing could be another solution to help lower the costs of production, which are significantly higher for cell and gene therapies than for other more established drug types.

The FDA is also hoping to get on the same page with other regulators so that developers could be more confident a product they gain approval for in one country would have a good chance of success in others.

Some of [these problems] may relate to how we can make gene therapies for small populations more widely available, Marks said. What may be a tiny population in the U.S. becomes a reasonable sized population when you go globally.

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'We have to find a way': FDA seeks solutions to aid bespoke gene therapy - BioPharma Dive

San Diego, CAThe annual Cell & Gene Meeting on the Mesa in San Diego kicked off this week with a packed schedule of sessions and some 40 company presentations that speak to the significant progress in these burgeoning therapeutic fields.

Organized by the Alliance for Regenerative Medicine, the program has attracted more than 1,700 attendees, 20% of whom are C-level executives. Although opting for a hybrid format, the enthusiastic number of live attendees signaled the thrill and benefits of live conferences and networking.

Commercialization is around the bend

The opening plenary session covered current trends and challenges surrounding gene therapy commercialization. Moderated by Dave Lennon, PhD, CEO of Satellite Bio, the panel discussed critical topics related to bringing these potentially life-changing treatments to market: pricing, the hurdles of early access, accelerated approval requirements, novel go-to-market challenges, and considerations of global equity.

Arguably the key rate-limiting step for commercialization is regulatory approval. Debbie Drane, senior vice president (SVP) of Global Commercial Development and Therapeutic Area (TA) Strategy at CSL Behring, discussed how regulators do not understand all diseases equally. Some of the targeted rare diseases do not have a clinical or regulatory precedent. Regardless of a regulatory bodys familiarity with a disease, Drane thinks making durability claims with gene editing can be tricky. For example, CSL Behrings EtranaDez, potentially the first gene therapy for patients living with hemophilia B, accepted by the FDA for priority review last May, will have to be compared to existing chronic treatments.

Regarding access to gene therapy before approval, Matthew Klein, MD, chief operating officer (COO) at PTC Therapeutics, said, Were in a special situation with one-time administered gene therapies. Thats different than when you have a repeat-administered small molecule, for example, where you can leverage compassionate use programs and expanded access programs to accelerate commercialization on the other side of approval. Obviously, with a one-time administrative therapy, you must think carefully about how that plays out.

Klein laid out PTCs different approaches, including early access programs to leverage treating patients before finalizing pricing and negotiation. Were looking to European countries like France with early access programs that allow us to provide commercial drugs prior to finalizing reimbursement discussions, he said.

Upon drug approval, one of the first things that happen is that patients and families worldwide start to reach out. According to Leslie Meltzer, PhD, chief medical officer (CMO) at Orchard Therapeutics, this is a relationship that needs to be cultivated from the earliest stages of development.

Meltzer said companies need to consider what questions the patient communities might have about the safety and efficacy of therapy and how to motivate participation in a corresponding clinical trial. Meltzer advocates for early and frequent patient engagement with a unified voice on the value of a gene therapy product. This can be transformative in reaching communities and setting expectations about timelines and whats involved with therapy.

The high price of one-shot cures

On pricing, Thomas Klima, Chief Commercial and Operating Officer of bluebird bio, discussed the pricing of the cell-based gene therapy product Zynteglo, approved by the FDA in August to treat beta-thalassemia, which will cost $2.8 million per patient. Klima highlighted that people with the most severe form of beta-thalassemia live their lives tethered to the healthcare system. They require regular transfusions and spend an average of 9.8 hours every three to four weeks in a hospital to receive the blood transfusions necessary for survival. Klima claimed that lifetime treatment for transfusion-dependent thalassemia costs more than $6 millionwhich is in line with the projection of $5.4 million from a recent study by Vertexand argued for the value of bluebirds treatment for $2.8 million.

For how commercialization models can expand and evolve, Christine Fox, president of Novartis Gene Therapies, said that part of the equation is bringing these treatments to countries around the world. At the heart of this problem is bringing patient advocacy and medical advisory to countries greatly affected by the clinical indication.

Overall, there was optimism that there would be an upswing in approved gene therapy products, as evidenced by a growing number of clinical trials using CRISPR gene editing. The first-ever approval of a CRISPR gene-editing therapy could be less than a year away. At the same time, base editing has already entered the clinic, and the first in vivo CRISPR approaches are progressing in clinical trials. This progress reflects how much has been learned in assembling the necessary pieces to get these treatments to commercialization, from development and manufacturing to the clinical and regulatory side of the equation.

More than one way to skin a [gene editing] cat

Another interesting session at the Cell & Gene Meeting on the Mesa offered forecasts of near- and longer-term future breakthroughs in clinical genome editing, featuring the CEOs of LogicBio, Homology Medicines, and Arbor Biotechnology as well as the CSO of Editas Medicine.

Devyn Smith, PhD, CEO at Arbor Biotechnologies, said investors understood the promise of genome editing, noting that the valuations of key public companies have held up remarkably well considering the market turmoil over the past two years. [It] is incumbent on all of us in this space to continue executing and hopefully generating positive clinical data so that momentum continues, Smith said.

Mark Shearman, PhD, CSO at Editas Medicine, agreed. With any new technology, the [focus is] on clinical data and proving that its safe and efficacious. Typically, [investors] also want to see a projection of where the programs going and a timeline over which youll be able to submit an application. Theyre also interested in whether you are in control of the technology and have all the infrastructures to monitor the technology to be confident that you can advance it. Lastly, if you have examples where a regulatory authority has reviewed your process and analytics, confidence boosts when approved or accepted.

Tim Farries, PhD, Principal Consultant and Senior Director with the consultancy Biopharma Excellence, also questioned the benefit of launching gene editing programs on rare diseases with small populations to show the relative ease and benefits before expanding to broader indications and populations. But for the most part, genome editing involves modifying DNA at one specific site. Thats why you see gene editing therapies in monogenic disorders right nowbecause you have to know exactly what part of the genome is contributing at a big effect size to the disease that youre trying to treat, said Albert Seymour, PhD, President and CEO at Homology Medicines. Thats a great place to start as we understand a little bit more about larger monogenic indications.

During a discussion on choosing between developing editing tools or understanding biological targets, all panelists hedged towards editing technology. Fred Chereau, president and CEO of LogicBio, favored starting with the editing technology because its where the safety concerns can emerge. Understanding an editing technologys efficiency and precision helps inform product development.

That said, each disease will require a different approach. According to Smith, certain indications will require a cut-and-kill approach to knock out or down a gene, changing an individual base or a series of bases, or impacting regulatory regions. The reality is there are going to be a lot of different ways weve got to skin this cat, and its not going to be one-size-fits-all, said Smith.

Another question addressed what payers would like to see gene editing show over the next three to five years. Shearman answered, For the rare disease area, this should get worked out pretty quickly because, ultimately, [it] wont be an issue of money based on the number of patients. I think the transition to treating large patient populations is going be an interesting one.

Smith said that someone could be wildly successful and completely upend the payers way of doing things. Its an opportunity for new upstarts to come in and figure out new different approaches to innovate, he said. On trying to fit the current approach to reimbursement into the one-and-done therapies, Smith added, its not even a square peg-round holetheyre in different planets. Something has got to give somewhere. This will require different thinking because applying existing models will limit access to patients.

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Approval, Commercialization Highlighted at Cell & Gene Meeting on the Mesa - Genetic Engineering & Biotechnology News

BEIJING & BURLINGTON, Mass.--(BUSINESS WIRE)--CANbridge Pharmaceuticals Inc. (HKEX:1228), a leading global biopharmaceutical company, with a foundation in China, committed to the research, development and commercialization of transformative rare disease and rare oncology therapies, announced that data from its gene therapy research agreement with the Horae Gene Therapy Center, at the UMass Chan Medical School, was presented at the 29th European Society of Gene and Cell Therapy Annual Congress in Edinburgh, Scotland, today.

In an oral presentation, Guangping Gao, Ph.D., Co-Director, Li Weibo Institute for Rare Diseases Research, Director, the Horae Gene Therapy Center and Viral Vector Core, Professor of Microbiology and Physiological Systems and Penelope Booth Rockwell Professor in Biomedical Research at UMass Chan Medical School, discussed the study that was led by the investigator Jun Xie, Ph.D., and his team from Dr. Gaos lab, and titled Endogenous human SMN1 promoter-driven gene replacement improves the efficacy and safety of AAV9-mediated gene therapy for spinal muscular atrophy (SMA) in mice.

The study showed that a novel second-generation self-complementary AAV9 gene therapy, expressing a codon-optimized human SMN1 gene. under the control of its endogenous promoter, (scAAV9-SMN1p-co-hSMN1), demonstrated superior safety, potency, and efficacy across several endpoints in an SMA mouse model, when compared to the benchmark vector, scAAV9-CMVen/CB-hSMN1, which is similar to the vector used in the gene therapy approved by the US Food and Drug Administration for the treatment of SMA. The benchmark vector expresses a human SMN1 transgene under a cytomegalovirus enhancer/chicken -actin promoter for ubiquitous expression in all cell types, whereas the second-generation vector utilizes the endogenous SMN1 promoter to control gene expression in different tissues. Compared to the benchmark vector, the second-generation vector resulted in a longer lifespan, better restoration of muscle function, and more complete neuromuscular junction innervation, without the liver toxicity seen with the benchmark vector.

This, the first data to be presented from the gene therapy research collaboration between CANbridge and the Gao Lab at the Horae Gene Therapy Center, was also presented at the American Society for Cellular and Gene Therapy (ASGCT) Annual Meeting in May 2022. Dr. Gao is a former ASCGT president.

Oral Presentation: Poster #: 0R57

Category: AAV next generation vectors

Presentation Date and Time: Thursday, October 13, 5:00 PM BST

Authors: Qing Xie, Hong Ma, Xiupeng Chen, Yunxiang Zhu, Yijie Ma, Leila Jalinous, Qin Su, Phillip Tai, Guangping Gao, Jun Xie

Abstracts are available on the ESGCT website: https://www.esgctcongress.com/

About the Horae Gene Therapy Center at UMass Chan Medical School

The faculty of the Horae Gene Therapy Center is dedicated to developing therapeutic approaches for rare inherited disease for which there is no cure. We utilize state of the art technologies to either genetically modulate mutated genes that produce disease-causing proteins or introduce a healthy copy of a gene if the mutation results in a non-functional protein. The Horae Gene Therapy Center faculty is interdisciplinary, including members from the departments of Pediatrics, Microbiology & Physiological Systems, Biochemistry & Molecular Pharmacology, Neurology, Medicine and Ophthalmology. Physicians and PhDs work together to address the medical needs of rare diseases, such as alpha 1-antitrypsin deficiency, Canavan disease, Tay-Sachs and Sandhoff diseases, retinitis pigmentosa, cystic fibrosis, amyotrophic lateral sclerosis, TNNT1 nemaline myopathy, Rett syndrome, NGLY1 deficiency, Pitt-Hopkins syndrome, maple syrup urine disease, sialidosis, GM3 synthase deficiency, Huntington disease, and others. More common diseases such as cardiac arrhythmia and hypercholesterolemia are also being investigated. The hope is to treat a wide spectrum of diseases by various gene therapeutic approaches. Additionally, the University of Massachusetts Chan Medical School conducts clinical trials on site and some of these trials are conducted by the investigators at The Horae Gene Therapy Center.

About CANbridge Pharmaceuticals Inc.

CANbridge Pharmaceuticals Inc. (HKEX:1228) is a global biopharmaceutical company, with a foundation in China, committed to the research, development and commercialization of transformative therapies for rare disease and rare oncology. CANbridge has a differentiated drug portfolio, with three approved drugs and a pipeline of 11 assets, targeting prevalent rare disease and rare oncology indications that have unmet needs and significant market potential. These include Hunter syndrome and other lysosomal storage disorders, complement-mediated disorders, hemophilia A, metabolic disorders, rare cholestatic liver diseases and neuromuscular diseases, as well as glioblastoma multiforme. CANbridge is also building next-generation gene therapy development capability through a combination of collaboration with world-leading researchers and biotech companies and internal capacity. CANbridges global partners include Apogenix, GC Pharma, Mirum, Wuxi Biologics, Privus, the UMass Chan Medical School and LogicBio.

For more on CANbridge Pharmaceuticals Inc., please go to: http://www.canbridgepharma.com.

Forward-Looking Statements

The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, we undertake no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, after the data on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development.

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CANbridge-UMass Chan Medical School Gene Therapy Research in Oral Presentation at the European Society of Gene and Cell Therapy (ESGCT) 29th Annual...

Depression Treatment: How Genetic Testing Can Help Find the Right Medication

Depression Treatment: How Genetic Testing Can Help Find the Right Medication

17 October,2022 08:42 am

ISLAMABAD, (Online) - Thats according to a new studyTrusted Source conducted by the U.S. Department of Veterans Affairs (VA) and published today in the Journal of the American Medical Association.

In it, researchers report that pharmacogenetic testing might help medical professionals by providing helpful information on how a person metabolizes a medication. This information can help doctors and others avoid prescribing antidepressants that could produce undesirable outcomes.

Depression medication is sometimes determined through trial and error to find the best drug and dosage. The researchers say they hope genetic testing can minimize this by giving insight into how a person may metabolize a drug.

Researchers said genetic testing did not show how a person would react to a particular medication but instead looked at how a person metabolized a drug. A drug-gene interaction is an association between a drug and a generic variation that may impact a persons response to that drug. Learning more about drug-gene interactions could potentially provide information on whether to prescribe medication and whether a dosage adjustment is needed.

In the study, around 2,000 people from 22 VA medical centers diagnosed with clinical depression received medications to treat their symptoms. The participants were randomized, with one-half receiving usual care and one-half undergoing pharmacogenetic testing.

For those that received usual care, doctors prescribed medication without the benefit of seeing a genetic testing result. The researchers found that 59 percent of the patients whose doctors received the genetic testing results used medications with no drug-gene interaction. Only 26 percent of the control group received drugs with no drug-gene interaction.

The researchers said the findings show that doctors avoided medications with a predicted drug-gene interaction.

Most often, patients get tested after at least one or two drugs havent worked or they had severe side effects, said Dr. David A. Merrill, a psychiatrist and director of the Pacific Neuroscience Institutes Pacific Brain Health Center at Providence Saint Johns Health Center in California. There are real genetically driven differences in how people metabolize drugs. It helps select more tolerable options to know about their genetics ahead of time.

Researchers interviewed participants about their depression symptoms at 12 weeks and 24 weeks.

Through 12 weeks, the participants who had genetic testing were more likely to have depression remission than those in the control group.

At 24 weeks, the outcome was not as pronounced. The researchers said this showed that genetic testing could relieve depressive symptoms faster than if a person did not receive the testing.

What experts think

There is a place for pharmacogenetic testing when treating people with depression, according to Dr; Alex Dimitriu, an expert in psychiatry and sleep medicine and founder of Menlo Park Psychiatry & Sleep Medicine in California and BrainfoodMD.

Some situations that might call for genetic testing include treatment-resistant depression and more complex cases.

It tells me if someone will either rapidly or slowly metabolize a drug meaning the level of the drug will either be too low or too high depending on the persons metabolism, Dimitriu told Healthline. I have used it in a few rare cases to see what options remain.

To me, more important than pharmacogenetic testing is watching the symptoms and response in my patients, he continued. I see my patients often, especially when starting a new medicine, and we can go slow and watch how the patient is doing. If you start at a low dose and raise the dose slowly, with good monitoring and charting, you can readily see who responds too fast or too slow and at what dose.

Some doctors dont think the science is there yet and arent going to rush into using pharmacogenetic testing based on this study.

I used pharmacogenetic testing about ten years ago and the science is accurate. It tells you the persons genetic makeup, said Dr. Ernest Rasyida, a psychiatrist at Providence St. Josephs Hospital.

From a scientific point of view, he told Healthline, this was a great study. It showed that the doctor used the data 60 percent of the time.

That means that the doctor looked at the data and the medications in the green zone and chose not to use them for side effects or other reasons. Instead, they chose a drug in the red zone because of their clinical experience.

I would argue that if 40 percent of the time you are going to use your judgment and you should use your judgment then why get the test? he concluded.

In addition to depression, pharmacogenetic testing can also be used in the treatment of other non-mental health conditions, such as cancer and heart disease.

Experts say there is no risk to the patient when getting the test and the researchers said they believe it will likely benefit some patients substantially.

Pharmacogenetic results are well-known and have been for years, but the clinical practice of medicine is very conservative, so it takes a long time for clearly beneficial changes to become common practice, Merrill told Healthline. If 15 to 20 percent of patients started on a new drug can avoid a major gene-drug interaction by knowing their results, doing the test seems like a no-brainer to me.

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Depression Treatment: How Genetic Testing Can Help Find the Right Medication - Dunya News

As activity in this space grows, so do the hurdles in moving these products forward.

Cell and gene therapy (CGT)its risks and promisesare succinctly summarized in this description of clinical trial number NCT01129544, a Phase I/II study in children born with X-linked severe combined immunodeficiency (SCID-X1), an inherited, rare, and life-threatening disease. The eight-person trial, which began in May 2010, continues today. The following paragraph has been edited.1

Gene transfer is still research for two reasons. One, not enough children have been studied to tell if the procedure is consistently successful. [And] we are still learning about its side effects and doing gene transfer safely. In previous trials, five children developed gene transfer-related leukemia; four are in remission; one died.

If the above information has stifled the research communitys scientific curiosity about CGT, it is not evident. Evidence from numerous sourcesClinicalTrials.gov, the Alliance for Regenerative Medicine (ARM), FDAare chock-a-block with studies, trials, and figures showing these therapies popularity. In the second quarter of 2022, 3,633 such treatments were in development, up from 1,745 in May 2021. The vast majority are in the preclinical stage.2,3

Some sources are revealing more.

Most indicate that academics now have a remarkable presence in the CGT development space, including sponsorship. Last year, for the first time, ARM included sponsorship figures in its twice-annual industry report.4 Academic- and government-sponsored trials far exceeded industry for sponsored trials in CGT. Stephen Majors, senior director for public affairs, ARM, says the alliance knew of academias presence for the past few years, but only was able to get data this year from its partner, Global Data.

Less reliable, but still noteworthy, are data from ClinicalTrials.gov: for active Phase I trials, industry has 89; others, which covers academia and government, have 50. Industry enrollment for Phase I is 172; others, 116.Phase III is one for others, eight for industry.

A little disruption in pharmas corner of the world? It seems that way. While basic bench to preclinical to clinical trial has long been the traditional route to FDA approvaland no one interviewed for this article suggested a reroutewhat it does imply is that pharma members have some competition from the spin-offs and academic biotechs that historically they have absorbed.

There are suspected trends that we are watching, says Majors.As to whether academias presence in this spot can be called a trend depends on ones definition of what a trend is. The Centers for Disease Control and Prevention (CDC) considers changes over a number years to determine a trend; financial investment firms typically evaluate over a two-year period.Considering that CGT companies raised $23.1 billion in 2021, 16% more than 2020,3 the answer to the above question could be, maybe.

The CGT space is still immature, according to Mike Rea, founder of Protodigm, a self-described exploratory research organization that partners with biopharma clients on alternative development and commercial solutions. Physicians need time to be comfortable with these therapies, notes Rea, so they may not be used on a regular basis.

For example, physicians have to understand how to deliver the gene, agrees cardiologist Arthur M. Feldman, MD, PhD, whose lab worked on a heart failure-related mutation in BAG3 for decades.

Last month, the company he founded, Renovacor, agreed to be acquired by Rocket Pharmaceuticals.5 We are asking physicians to do something they never did before and to understand a very different set of information, including risk/benefit discussions that they didnt learn about in medical school, he says. Feldman is a Laura H. Carnell Professor of Medicine, Division of Cardiology, and a member of the Center for Neurovirology and Gene Editing at the Lewis Katz School of Medicine at Temple University.

Chris Learn, Parexels vice president of cell and gene therapy, is unequivocal regarding academias increased presence in the drug development space focused around these treatments. He cites MD Anderson and Moffitt Cancer Center as two institutions that are sponsoring their own trials. The lines are really blurring here, he tells Applied Clinical Trials. It is indisputable.

The following is a look at how academia is showing up in various reports.

In its 2022 report4, ARM separated sponsorship, type of therapygene, cell-based, and tissue engineeringand trial phase. What these data show are industry far exceeding academic and government sponsored trials for gene therapy, while for cell therapy alone, the reverse is true: 656 cell therapy trials for academic and government, and 424 for industry. For gene therapy, there are 84 for the academics and government, and 222 for industry. In a later report, ARM found non-industry trials dropped.

Pharma Intelligences Pharma R&D Annual Review does not break down trials by their sponsors. It does, however, break down whats in the pipeline in various categories, including by the number of therapies per company, and by disease type.6 In numbers captured prior to March 2020, the analysis reported 1,849 companies with asingle drug in its pipeline, up from 1,633 in 2019, comprising more than half of all drug companies. As for types of therapies, gene therapy was in third place, the same spot it occupied in 2019. (Cancer-related therapies occupy the top spots.) Overall, biotech therapies in the pipeline increased by 13.2% in 2020 over 20196,135 vs. 5,422. Cellular therapy, the field in which academia is dominating, rose to 14th place, up from 33.

In 1982, Feldman was a resident in the cardiac care unit at the Johns Hopkins Hospital in Baltimore when he took care of a 22-year-old woman, a native Pennsylvanian, who was dying of heart failure. Sadly, we didnt have drugs with which to treat her, he recalls. Feldmans involvement with the case and the womans family led to his career as a cardiologist, he says. Twenty years later in Philadelphia, he was asked to see a heart-failure patient in consult, who turned out to be the aunt of the younger woman. It would take almost another 10 years until the technology became available to identify the genomic anomaly in this family. Here, a genetic variant that is produced by one of two alleles causes the protein product to be unstable. The result: the cell removes it, so the person with the variant has just half the amount of required protein.

BAG3 is an interesting protein that is found in the heart, the skeletal muscles, and the nervous system, including the brain. Its function is to help remove degraded and misfolded proteins, stop apoptosis or programmed cell death, and maintain the structure of the skeletal muscles. A missing allele isnt the only genetic cause for heart failure, Feldman said. Other patients, while having the correct amount of DNA, have a point mutationa single amino acidin half of the produced DNA. That single letter is the wrong amino acid in the specific site in the protein.

Around this time, Kamel Khalili, PhD, Laura H. Carnell Professor, and chair of the department of microbiology, immunology, and inflammation; director of the Center for Neurovirology and Gene Editing; and director of the Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine, Temple University, had created a method by which he could excise the HIV virus from patients using the new technique of CRISPR-Cas9.

Khalili believes that BAG3 may be involved in the pathogenesis of HIV-1 in brain diseases and protein quality control caused by viral infection as well as several other disorders, including Alzheimers disease and dementia. BAG3 changes the homeostasis of the cell, he says. The only solution is to fix the cell. Khalili has used CRISPR technology to excise the viral genome in both small and large investigational animals and has recently started a Phase I trial to test the safety of the new gene-editing treatment. Khalili, too, started a company, but Temple holds the license. In the case of Renovacor, it was granted the license by Temple.

As a scientist, when you are doing something in biomed research, [the] goal is to translate bench work to the clinic for [the] wellness of people. We are doing long hours and long days because we want to help. We are trying to see if discovery can help people, says Khalili. I know my limit, I stop at business aspects. My interest is to discover research which can help populations.

Was Feldman happy with his business experience? As a company gets bigger, others join the team who fulfill other roles, like acquiring funding or developing the actual product, he says. Releasing the control reins are difficult. But if it speeds up the timeline to get an approved product into the clinic, then its all worth it, he adds.

Researchers such as Feldman and Khalili, says Kaspar Mossman, PhD, director of communications and marketing at QB3, a University of California biotech accelerator, are normally not deeply interested in business. He notes the new flagship space in UC Berkeley called Bakar Lab. So far, it has 25 companies, one-third from university labs. They collaborate, they share equipment, [at times] they merge, Mossman tells Applied Clinical Trials.

And, he adds, Academics tend to be very smart individuals. The more time they spend in business, they learn stuff and become serial founders, says Mossman. They are honest about not wanting to be a CEO.

In terms of business, the academics employers are also pretty smart. The huge bugaboo with CGT commercialization is the manufacturing processthe need for an apheresis unit, ultra-cold storage, and regulated cell processing facilities.

Some institutions are building their own manufacturing facilities to more easily meet the increasingly complicated standards pertaining to regenerative medicine production. Harvard, MD Anderson, Moffitt, the University of Pennsylvania, and the University Hospital of Liege in Belgium8 all have or are planning to build their own facilities.

As for how academias presence impacts the traditional pharma space, those interviewed cited pros and cons. More research is better, more companies vying for venture capital funding is not. But more trials mean more competition among similar therapies, which, says Majors, is a good thing.

We need experimentation, adds Rea. If left to pharma, he says, the research wouldnt happen. Smaller biotechs are taking the risk. Over the last 10 years, Rea believes pharma has been slow in the risk-taking department. Once upon a time, pharma didnt have many competitors. Now, with many numerous smaller companies with viable assets, willing to accept a smaller net profit, the competition is creating some angst. Pharma cant project everyones movement, says Rea. The gene/cell therapy landscape [for products] is huge.

Likely adding to the angst: Those smaller biotechs are getting financial help. Between April 4, 2021, and June 24, 2021, of 23 start-up financing deals, 19 involved academics.2

Learns viewpoint is different. He says there are too many players out there, and while large pharma may be averse to risk, I really do believe what we are witnessing are simply market forces that have played into this. There is so much cash coming in, he continues, that people can be blinded by the pitfalls. The CGT area, he adds, is bloated and he says the industry needs an overall strategy.

Learn doesnt think that academias presence in the CGT space is a flash in the proverbial pan. The enthusiasm to find cures is real, and some research institutions have the endowments to see the trials through. I think it is just the beginning, says Learn. Academia will put their futures in front of them. Why put all your sweat equity into it and not have any fiduciary benefit of the approved product?

In Pharma Intelligences 2020 Pharma R&D Review, its author questioned the wisdom of so many drugs, overall, in the pipeline4,001 added in 2018 and 4,730 added in 2019, for a total of 17,737 drug candidates. [A]re the industrys eyes getting too big for its belly? Unless it can continue to provide [approved therapies] then a certain degree of control in the pipeline might be advisable, the report stated.6

And now to costs. While no one doubts these cures change lives, the question of access persists. FDAs approval of Bluebird Bios second therapy this year, branded as Skysona, for early but active cerebral adrenoleukodystrophy, is expected to cost $3 million. Learn doubts that payers are jumping up and down to get Skysona on their formularies.

Its still a fairly dicey business proposition for companies to invest in this field, Steven Pearson, MD, president of the Institute for Clinical and Economic Review (ICER), said recently.8Theres still a risk that next-generation therapies will not flourish even in developed countries health systems, he added.

One positive development in the US, however, occurred late last month when Congress reauthorized the Prescription Drug User Fee Act (PDUFA) for the next five years, 2023-2027. The action maintained FDAs authority to collect fees from manufacturers and keep and recruit agency staff to review the increased number of CGT applications. Majors says most of FDAs review of CGT products involves scalability and consistent reproducibility in the manufacturing process, which, of course, means traveling.

According to a Senate press release9, FDA is seeking to hire at least 320 new staff members. In a statement, Pharmaceutical Research and Manufacturers of America (PhRMA) said a modern regulatory framework supported by PDUFA helps ensure patients have timely access to lifesaving medicines.

PDUFA reauthorization aside, there is little argument that the field of CGT, from research and drug discovery through commercialization, is advancing rapidly. In turn, so are the unique operational and manufacturing challenges that these therapies present. This reality may thin the currently crowded playing field in CGT going forward, with those sponsors and partners best prepared to deliver on the numerous touchpoints required separating from the pack.

Christine Bahls, Freelance Writer for Medical, Clinical Trials, and Pharma Information

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The Risk-Reward Proposition for CGT Clinical Trials - Applied Clinical Trials Online