Category Archives: Gene Medicine

Mount Sinai researchers conducting clinical trials of a drug targeting a cancer gene found that it increased metastatic cancer patients survival and was able to work within the brain.

Mount Sinai researchers conducting clinical trials of a drug targeting a cancer gene found that it increased metastatic cancer patients survival and was able to work within the brain, according to a study published in Clinical Cancer Research in February.

The drug entrectinib targets cancers that involve fusions between the cancer gene NTRK and other genes, including certain types of lung, breast, colon, and other cancers. This study looked into the effectiveness of the drug a year after three clinical trials were completed and found patients response rates post-trial were 60 percent.

A significant finding in this study, which was not seen in the initial trials, was that the drug is able to cross the blood-brain barrier effectively. Researchers found evidence that the therapy was working against metastatic cancer that spread to the brain.

This is the largest study evaluating the safety and activity of entrectinib in NTRKfusion-positive solid tumors, said Christian Rolfo, MD, PhD, MBA, Professor of Medicine (Hematology and Medical Oncology) at the Icahn School of Medicine at Mount Sinai and Associate Director for Clinical Research in the Center for Thoracic Oncology at The Tisch Cancer Institute. The confirmation of substantial effect on metastases in the brain suggests that entrectinib could address the unmet need of an effective treatment for patients with NTRK fusion-positive tumors that spread to the central nervous system. Although NTRK fusions are rare, our results should encourage broader screening for these fusions in patients with solid tumors as they may benefit from entrectinib, particularly because the extended life expectancy of these patients may increase the likelihood of metastases in the brain.

Gene fusions involving NTRK can be associated with a large range of tumor types. They occur in 90 percent of rare pediatric tumors and rarer subtypes of breast cancers and salivary cancers.

This international study was conducted in several institutions in collaboration with investigators from Dana Dana-Farber Cancer Institute, Ludwig Center at Harvard Medical School, and other international centers. The research was funded by F. Hoffmann-La Roche Ltd.

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Molecular Treatment Is Able to Control Brain Metastasis of Different Tumors - OncLive

Findings from the BIONIKK study published in The Lancet Oncology suggest that biomarker-driven treatment selection based on tumor molecular phenotype may be on the horizon in the treatment paradigm for metastatic renal cell carcinoma (RCC).1

The study (NCT02960906) specifically examined this precision medicine pathway in the context of treatment selection between nivolumab (Opdivo) with or without ipilimumab (Yervoy) and a VEGFR tyrosine kinase inhibitor (TKI) in the first-line setting for patients with metastatic clear-cell RCC (ccRCC).

Frontline treatment of ccRCC has changed tremendously since 2015, when the immune checkpoint inhibitor (ICI), nivolumab, was granted FDA approval. Since then, ICIs alone and in combinations have entered the space and offer options for patients with RCC subtypes.

Prior research showed that treatment with sunitinib (Sutent) in patients with good response to the agent had molecular and pathological features closest to normal kidney tissue (ccrcc3), investigators hypothesized that immune-high ccrcc4 tumors would respond to nivolumab-based therapy, either with or without ipilimumab (Yervoy), because of theimmune-enriched tumor microenvironment. Moreover, ccrcc1 tumors would have a better response to the combination of nivolumab and ipilimumab compared with nivolumab alone because of the need to recruit antitumor cytotoxic T cells.

To our knowledge, this is the first study to show the feasibility of prospective patient and treatment selection based on tumor gene expression in metastatic renal cell carcinoma. By allocating treatment according to tumor molecular group, we enriched the population who achieved an objective response with nivolumab, nivolumabipilimumab, and VEGFR tyrosine kinase inhibitors (VEGFR-TKIs), wrote the study authors led by Yann-Alexandre Vano, a medical oncologist at the Hpital Europen Georges-Pompidou.

To conduct the biomarker-driven, open-label, noncomparative, randomized, phase 2 BIONIKK trial (NCT02960906), patients with ccRCC from 15 university hospitals and cancer centers in France were enrolled. Those eligible for the study were patients aged 18 years or older who had newly diagnosed or recurrent stage IV RCC, an ECOG performance status of 0-2, 1 or more measurable lesion per RECIST v1.1, and had not received previous systemic therapy for metastatic disease.

In terms of molecular grouping, the presence of a sarcomatoid component and PD-L1 expression was centrally assessed by an expert uropathologist on selected formalin-fixed paraffin-embedded tumor samples for all patients. Samples were selected by certain criteria, which included tumors with 60% of viable tumor cells, 20% of necrosis, of highest grade, and with the highest immune infiltrate. Also, the presence of a sarcomatoid component was identified and PD-L1 expression was assessed using the PD-L1 22C3 antibody. Tumors with TC 1% were PD-L1 positive.

The patients with ccrcc1 and ccrcc4 disease were assigned to receive either nivolumab 3 mg/kg or nivolumab with ipilimumab 1 mg/kg. Those with ccrcc2 and ccrcc3 groups disease were assigned to receive 1 of 2 VEGFR TKIs (sunitinib 50 mg/day for 4 weeks every 6 weeks or oral pazopanib [Votrient] 800 mg daily continuously).

The primary end point of the study was the objective response rate (ORR) by investigator assessment per RECIST v1.1. Secondary end points of the study included ORR at week 22, progression-free survival (PFS), overall survival, duration of response (DOR), duration of treatment, and safety and tolerability.

Overall, there were 61 patients assigned to receive nivolumab monotherapy, 101 assigned to the combination of nivolumab and ipilimumab, and 40 received a VEGFR TKI.

Among patients with ccrcc1, those treated with nivolumab alone had an ORR of 29% (95% CI, 16%-45%) vs 39% (95% CI, 24%-55%) with nivolumab plus ipilimumab (Odds ratio [OR], 0.63; 95% CI, 0.25-1.56). Patients with ccrcc4 disease had an ORR of 44% (95%, 20%-70%) on nivolumab monotherapy vs 50% (95% CI, 26%-74%) in patients treated with nivolumab/ipilimumab (OR, 0.78; 95% CI, 0.20-3.01).

Responses were higher among patients with ccrcc2 compared with other phenotypes and lower in patients with ccrcc3 disease. Specifically, those with ccrcc2 treated with a VEGFR TKI had an ORR of (50% (95%, 33%-67%) vs 51% (95% CI, 34%-68%) with nivolumab plus ipilimumab (OR, 0.95 (0.38-2.37). Among the patients with ccrcc3, the ORR was 0 with VEGFR TKI therapy compared with 20% (95% CI, 1%-72%; OR, not evaluable [NE]).

DORs were not reached (NR) in any treatment arm, but ranged from 6.0 months to 11.8 months, depending on phenotype and the treatment administered. The shortest time to response was observed in patients with ccrcc4 disease treated with nivolumab monotherapy, with a time to response of 2.2 months (range, 2.2-NR). The longest time to response was among patients with ccrcc2 disease treated with a VEGFR TKI at 4.9 months (range, 2.8-16.5).

PFS was assessed in the ccrcc1, ccrcc2, and ccrcc4 groups. In patients with ccrcc1 disease who received the combination of nivolumab and ipilimumab, the median PFS was 7.7 months (95% CI, 5.0-12.9) compared with 5.2 months (95% CI, 2.4-9.1) among those treated with nivolumab alone (hazard ratio [HR] 1.27 (95% CI, 0.77-2.11).

The median PFS in patients with ccrcc4 treated with the ICI combination was 13.0 months (95%CI, 2.5-NE) vs 7.8 months (95% CI, 2.3-NE) with nivolumab alone (HR, 1.37 (95% CI, 0.57-3.29)

Finally, patients in the ccrcc2 group treated with nivolumab plus ipilimumab had a median PFS of 11.1 months (95% CI, 7.7-23.2) vs 14.4 months (10.6-NE) with VEGFR TKI treatment (HR, 0.75; 95% CI, 0.40-1.39).

Safety was assessed based on treatment with the nivolumab monotherapy, nivolumab plus ipilimumab, and VEGFR TKI therapy, and grade 1/2 adverse events (AEs) were observed in 76%, 54%, and 30% respectively. In the nivolumab-only group, the most common low-grade AEs were fatigue (50%), pruritus (24%), and maculopapular rash (17%). For patients treated with the ICI combination, the most common grade 1/2 AEs were fatigue (50%), pruritus (31%), and diarrhea (32%). Lastly, in the VEGFR TKI arms, the most common grade 1/2 AEs were fatigue (65%), diarrhea (53%), and oral mucositis (43%).

Our results confirm that the response to nivolumab alone or with ipilimumab and to VEGFR-TKIs is different depending on the characteristics of the tumor and its microenvironment. The feasibility of prospectively selecting patients by their molecular group for treatment choice opens the way to larger biomarker-based trial designs, wrote Vano et al.

Reference

1. Vano Y, Elaidi R, Bennamoun M, et al. Nivolumab, nivolumabipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): A biomarker-driven, open-label, non-comparative, randomized, phase 2 trial [Published online ahead of print April 04, 2022].Lancet Oncol. doi: 10.1016/s1470-2045(22)00128-0

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Study shows feasibility of mRCC treatment selection based on tumor gene expression - Urology Times

CAMBRIDGE, Mass., May 03, 2022 (GLOBE NEWSWIRE) -- Ring Therapeutics, a life sciences company founded by Flagship Pioneering to revolutionize gene therapy with its AnellogyTM commensal virome platform, today announced two upcoming presentations at the 25th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT), to be held from May 16-19, 2022 in Washinton, DC. These presentations further demonstrate the potential of Rings AnellogyTM platform in harnessing the unique biology of anelloviruses to engineer the novel precision medicines.

Poster Presentations:

Title: Favorable immune profile of anelloviruses makes them attractive candidates as gene therapy vectorsSession Title: Immunological Aspects of Gene Therapy and Vaccines IAbstract Number: 713Board number: TU-218Presenter: Harish SwaminathanPresentation Date and Time: Tuesday, May 17, 2022, 5:30 - 6:30 p.m. ET

This poster presents data from a study that characterized the immunogenicity of anelloviruses and the antigenic profile of anellovirus proteins. Results showcase the favorable immune profile of anelloviruses.

Title: A novel gene delivery vector with low pre-existing immunity in humansSession Title: Vector Product Engineering, Development or Manufacturing IIIAbstract Number: 1158Board number: W-284Presenter: Dhananjay NawandarPresentation Date and Time: Wednesday, May 18, 2022, 5:30 - 6:30 p.m. ET

Data in this poster show successful vectorization of synthetically produced anelloviruses to produce the first AnelloVectorTM therapeutic. These novel vectors can successfully target a variety of tissues, and no pre-existing immunity in humans is observed.

About Ring TherapeuticsRing Therapeutics is revolutionizing the gene therapy and nucleic acid medicine space by harnessing the most abundant and diverse member of the human commensal virome, anelloviruses. The company developed the Anellogy platform which focuses on anelloviruses to potentially treat a broad range of diseases. Through harnessing the unique properties of these commensal viruses, the Anellogy platform generates diverse vectors that exhibit both tissue-specific tropism and the potential to be re-dosed. Ring Therapeutics, founded by Flagship Pioneering in 2017, aims to develop and further expand its portfolio by leveraging its platform to unlock the full potential of gene therapy and nucleic acid medicines, enabling a variety of mechanisms that successfully deliver therapeutic cargo to unreachable organs and tissues. To learn more, visit https://www.ringtx.com/ or follow us on Twitter at @Ring_tx.

Ring Therapeutics Media:Brittany Leigh, Ph.D.LifeSci Communicationsbleigh@lifescicomms.com+1-813-767-7801

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Ring Therapeutics Announces Two Presentations at the Upcoming 25th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT) -...

BOSTON--(BUSINESS WIRE)--Kelonia Therapeutics, a biotech company revolutionizing in vivo gene delivery, launched today with a $50 million Series A financing to usher in a new era of genetic medicines for a wide range of diseases. Kelonias platform overcomes the central challenge that has prevented the full realization of gene therapy for patients. Despite life-changing responses, existing gene therapies are highly complex, costly, and limited by complicated treatment paradigms, tractable therapeutic applications, and dose-limiting toxicities. By enabling precisely targeted, highly efficient, manufacturable off-the-shelf in vivo gene delivery, Kelonias technology has the potential to dramatically expand the impact and reach of genetic medicines to every patient in need.

Kelonia is backed by a strong syndicate of investors with a track record of successfully launching and building disruptive biotech companies. Alta Partners, Horizons Ventures, Venrock and other investors participated in the Series A round. The company will use the funding to redefine whats possible for genetic medicines starting with an off-the-shelf chimeric antigen receptor (CAR) to treat hematologic cancer that may enable the unrivalled clinical benefit of CAR T without the typical toxicities and with the ease of access of conventional medicines. Additionally, the company will advance other programs for oncology and non-oncology indications, and further expand its gene delivery platform and capabilities.

The cell and gene therapy field has been searching for solutions to durable in vivo genetic modifications regardless of whether applying gene editing, RNA expression or viral-mediated gene integration, said Kevin Friedman, Ph.D., President and Chief Scientific Officer of Kelonia. At Kelonia, we believe we have found an in vivo gene delivery solution that is safe, effective, and manufacturable for broad therapeutic application. With our Series A funding and key strategic collaborations, we will advance our lead product candidate toward clinical studies and further optimize our technology to explore treating diseases never thought possible with genetic medicines.

Based on discoveries made in the lab of Massachusetts Institute of Technologys Michael Birnbaum, Ph.D., and leveraging pioneering research from leading scientists at the French National Centre for Scientific Research (CNRS), Kelonias in vivo gene delivery technology enables a few potent lentiviral vector-like particles armed with an adjustable targeting system to precisely, efficiently, and safely deliver payloads exactly where needed to treat a broad range of diseases. The companys early applications combine oncology-targeted therapeutics, such as CAR and T cell receptor molecules, with Kelonias precision in vivo targeting technology. When used in concert, this combination enables potent and precise tumor targeting with limited off-tumor toxicity, which would otherwise be a concern. Administered directly in vivo as an off-the-shelf medicine, Kelonias transformational therapies in development for solid and hematologic tumors have the potential to democratize patient access to genetic medicines. Beyond oncology, the company will advance its technology to unlock delivery to previously hard-to-reach tissues, such as neurological, muscular or renal, to deliver different types of genetic cargo with the goal of radically transforming the treatment of diseases in these areas.

It turns out, a relatively simple and elegant idea to de-target and redirect lentivirus-like particles based on recently published research from my lab can potentially provide a solution to in vivo gene delivery, said Dr. Birnbaum, Ph.D., Co-Founder of Kelonia. Im incredibly excited about the potential of Kelonias platform and team to vastly expand the utility of gene therapies to treat oncology, autoimmune disease, rare monogenic or other diseases currently intractable to gene therapies.

Kelonia is combining the two crucial elements required to develop truly novel medicines: breakthrough biology and an exceptional team, said Bryan Roberts, Partner at Venrock. Michael Birnbaums industrially robust platform affords a targeting specificity log orders better than anything else out there and the team has a stellar track record for translating groundbreaking scientific gene therapy discoveries into viable products that are transformative for patients.

Strategic Collaborations

In addition to the completion of its Series A, Kelonia has established strategic collaborations with Adimab and ElevateBio. With both collaborations already successfully underway, each of these outstanding partners brings differentiating capabilities that enable and accelerate the companys vision to bring breakthrough genetic medicines to patients.

Adimab is the leading provider of therapeutic antibody discovery and engineering technologies. Kelonia will leverage Adimabs expertise and proprietary technologies, across a range of applications, to access tissue-specific antibodies that enable unlocking precise in vivo gene delivery to different tissues as well as antibodies that can be leveraged within the therapeutic genetic cargo.

ElevateBio is a technology-driven company focused on powering transformative cell and gene therapies with multiple next-generation technology platforms and a fully integrated R&D and manufacturing facility. Through an expanding partnership, Kelonia will utilize ElevateBios lentiviral vector platform, process and analytical development expertise, and cGMP manufacturing capabilities to develop and advance novel manufacturing processes for Kelonia and manufacture of Kelonias products.

Leadership and Founding Team

Kelonia brings together industry leaders in cell and gene therapy responsible for the discovery and development of multiple clinical and commercial products including ABECMA, the first FDA-approved anti-BCMA CAR T cell therapy product for relapsed or refractory multiple myeloma. The companys leadership team includes Kevin Friedman, Ph.D., President and Chief Scientific Officer, Thomas Galbo, Ph.D., Chief Business Officer, and Molly Perkins, Ph.D., Vice President of Research.

Kelonias scientific founders include Michael Birnbaum, Ph.D., Associate Professor of Biological Engineering, Massachusetts Institute of Technology, and Michael Fischbach, Ph.D., Associate Professor of Bioengineering and of Medicine, Stanford University, both world-leading experts in the fields of microbiology, immunology, oncology, and cell and gene engineering.

The companys board of directors comprises Michael Birnbaum, Michael Fischbach, Kevin Friedman, Bryan Roberts and Bob More, Managing Director at Alta.

About Kelonia TherapeuticsKelonia is pioneering a new wave of genetic medicines using its next generation gene delivery platform. The companys simple and elegant cutting-edge in vivo gene delivery technology uses a few potent lentiviral vector-like particles to precisely and efficiently deliver in vivo genetic cargo to the desired target tissue, and only that tissue, every time. With an initial focus on developing transformational therapies for solid tumors and hematologic cancers, Kelonia is building a pipeline of genetic medicines for a wide range of diseases, with the bold goal of bringing genetic medicines to every patient in need. Learn more about Kelonia at http://www.keloniatx.com and follow us on LinkedIn and Twitter.

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Kelonia Therapeutics Launches with $50 Million Series A Financing to Pioneer Precision Targeted Genetic Medicines - Business Wire

NEW YORK & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Apertura Gene Therapy, a biotechnology company opening opportunities for treating debilitating diseases with limited options for patients, today announced that it has launched with a Series A financing of up to $67M from Deerfield Management Company to develop genetic medicines using platform technologies that address key limitations of genetic medicine delivery and expression. Deerfield Management has also committed additional operational support to further strengthen the companys ability to advance gene therapy discoveries.

Apertura is founded on a pair of platform technologies developed in the labs of Ben Deverman, Ph.D., Senior Director of Vector Engineering and Institute Scientist at the Broad Institute of MIT and Harvard, and Michael Greenberg, Ph.D., the Nathan Marsh Pusey Professor of Neurobiology and Chair of the Department of Neurobiology at Harvard Medical School (HMS). The companys platform leverages machine learning and high-throughput assays to engineer novel capsids, gene regulatory elements, such as promoters and enhancers, and payloads to simultaneously enhance multiple functions of gene therapies for greater translational potential.

With these platform technologies from the Broad Institute and Harvard University, Deerfield saw an opportunity to bring together and support a unique and comprehensive platform that could address technical challenges that have prevented gene therapy from reaching its full potential, said Dave Greenwald, Ph.D., Acting Chief Executive Officer of Apertura and Vice President, Business Development at Deerfield Management Company. While next-generation approaches to gene therapy have largely focused on the innovation of delivery vectors, Apertura has the potential to innovate simultaneously across delivery, expression, and payloads.

Ben Deverman, Scientific Founder of Apertura, said: When developing a gene therapy, it has been common to use naturally occurring serotype AAV capsids. The technology we have developed uses proprietary assays and machine learning to design custom AAV capsids that have the chosen characteristics for treating specific diseases, and we believe this approach will result in new and effective gene therapies.

Apertura has certain exclusive rights to AAV capsids developed in the Deverman Lab at the Broad Institute.

A separate sponsored research and licensing agreement with Harvard University, spearheaded by the Harvard Office of Technology Development, grants Apertura exclusive access to certain powerful methods of identifying cell type-specific genetic regulatory elements (GREs), including access to the Paralleled Enhancer Single-Cell Assay (PESCA) platform, developed in the Greenberg Lab at Harvard University.

A major challenge in developing effective gene therapies is having the payload of the therapy expressed at the correct level in target cells, said Greenberg. "The technology we have developed at Harvard Medical School overcomes this hurdle by targeting transgene expression to specific cell types, fine-tuning expression levels in these cells, and, at the same time, avoiding expression of the transgene in non-target cell types. The Greenberg labs PESCA platform was advanced to commercial readiness through the strategic support of the Q-FASTR program at HMS and the Blavatnik Biomedical Accelerator at Harvard University.

The two technology platforms have unique capabilities to simultaneously engineer AAV capsids to exhibit enhanced cellular tropism, evasion of pre-existing immunity, while maintaining and potentially improving manufacturability. The companys GRE platform focuses on GREs and enhancers that drive cell type-specific expression, disease state-specific expression, and tunable expression levels. These capabilities together are expected to enable Apertura to develop best-in-class gene therapies designed for specific indications.

Our platform has the potential to unlock many new indications for gene therapy, said Kristina Wang, Director of Corporate Development and Board Member of Apertura. We aim to maximize our impact through dedicated internal programs and meaningful partnerships with other biopharma companies and academic groups. Committed to advancing the field of gene therapy, Apertura seeks to collaborate broadly to accelerate impact to patients.

About Apertura Gene TherapyApertura is a biotechnology company opening opportunities for treating currently intractable diseases. We are uniquely positioned to develop genetic medicines by simultaneously engineering AAV capsids, genetic regulatory elements, and payloads to overcome limitations in cellular access, gene expression, pre-existing immunity, and manufacturability. Apertura is committed to growing the field of gene therapy and believes that together we maximize our impact by working with corporate and academic partners, patients, and foundations. Founded on technologies from the Broad Institute and Harvard University, and with support from Deerfield Management Company, the company is based at the Cure, Deerfields innovation campus in New York City. For more information, please visit our website at http://www.aperturagtx.com and follow us on LinkedIn and Twitter.

About Deerfield ManagementDeerfield is an investment management firm committed to advancing healthcare through investment, information and philanthropy. The Firm works across the healthcare ecosystem to connect people, capital, ideas and technology in bold, collaborative and inclusive ways. For more information, please visit https://deerfield.com/.

About Harvard Universitys Office of Technology DevelopmentHarvards Office of Technology Development (OTD) promotes the public good by fostering innovation and translating new inventions made at Harvard University into useful products that are available and beneficial to society. Our integrated approach to technology development comprises sponsored research and corporate alliances, intellectual property management, and technology commercialization through venture creation and licensing. More than 90 startups have launched to commercialize Harvard technologies in the past 5 years, collectively raising more than $4.5 billion in financing. To further bridge the academic-industry development gap, Harvard OTD manages the Blavatnik Biomedical Accelerator and the Physical Sciences & Engineering Accelerator. For more information, please visit https://otd.harvard.edu.

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Apertura Gene Therapy Launches with $67M Series A Financing from Deerfield and an Innovative Technology Platform to Develop Genetic Medicines -...

The repair of old, damaged, or diseased tissues using gene or cell therapies promises a future where people live longer, healthier lives and Ireland is well placed to become a manufacturing hub for products based on this technology.

Gene therapy is the technology used to correct a gene defect that is causing an inherited genetic disease. Cell therapy is the use of living cells from the patient or a donor, to repair tissue or treat an inflammatory condition or disease. These therapies can be used alone or combined for greater effect.

Weve been interested, for a very long time in the development of new treatments for patients involving cell and gene therapy, says professor of cellular therapy at NUI Galway Frank Barry a co-founder of the Regenerative Medicine Institute (Remedi) in 2004.

Over the last several decades there have been some extraordinary, transformative developments in medicine; for example, antibiotics and monoclonal antibodies and these have had a dramatic impact on how diseases were treated, says Barry. Many people believe that cell and gene therapy represent the next transformative innovation that will change medicine.

There are many examples of outstanding success stories, where diseases which were previously untreatable are now actually being treated and were very anxious to continue to play a role in this, says Barry.

The combination of cell and gene therapy has been successful in treating cancers that were thought incurable. For example, stem cells have been taken from the blood of patients with specific cancers, genetically modified so they target a particular cancer, and are delivered back into the patients blood.

Gene therapy has had a troubled history with some adverse outcomes reported from early clinical trials two decades ago. Most notably, and tragically, was the case of 18-year-old Jesse Gelsinger, who died in 1999 during a University of Pennsylvania run gene therapy trial. Jesse suffered from a genetic disease affecting his liver which meant that he was unable to metabolise ammonia.

The learnings from that have proven to be very helpful not to diminish the impact of his death on his family and the tragedy of that, says Prof Tim OBrien, head of medicine at NUI Galway, an Irish pioneer of this field.

In Ireland, the origins of cell and gene therapy research go back to 2004, when Remedi was set up with funding from Science Foundation Ireland (SFI). Then in 2014, the Centre for Cell Manufacturing in Ireland (CCMI) was established. Barry and OBrien have been the key figures driving the process.

From the beginning, the dream of Barry and OBrien was to convert promising gene and cell therapy research into new therapies that could then be tested in clinical trials. Galway was a good place to do it, as it was known as a leading hub for medical device research and manufacturing, and it had the laboratories, hospital tissue facilities and clinical trial expertise that would be required.

Almost two decades down the road, the next step, they say, requires putting in place a national plan for developing a cell and gene therapy industry across the island similar to what has been achieved for medical devices and other high areas dependent on advanced technology, like ICT and pharmaceuticals. The UK offers a model of what can be achieved as it benefits from a decision by government to heavily invest in gene and cell therapy 15 years ago through an independent body it established called the Cell and Gene Therapy Catapult.

The opportunity for gene and cell therapy to grow here in coming years helped attract Dr Meadhbh Brennan, a post-doctoral researcher at Harvard University, back to Ireland. She also worked at the National Institute of Health and Inserm in France before returning to NUIG to set up her own research group.

In France, Brennan had worked on a clinical trial using stem cells to treat bone defects, while in the US her research focused on factors secreted by stem cells which could be used as a therapeutic. While in the US, she was awarded funding from SFI and that provided impetus for her move home, to take up a position at NUIG working at the interface between engineering and medicine.

She has a European Research Council starting grant award to investigate ways of regenerating bone defects, building on her work in this area. There are more than one million bone grafting procedures performed annually in Europe, and after blood, bone is the most transplanted tissue. There are issues with these procedures, however, as bone tissue is limited in quantity and quality and there is often pain at the surgical site for patients.

Brennan and her team are seeking alternatives to bone grafting through the use of byproducts from the manufacturing of stem cells called extracellular vesicles (EVs). These EVs are tiny biological packages that each contain a therapeutic cargo that has been shown to be capable of enhancing healing processes in tissues by delivering healing messages from cell to cell.

Up to now, EVs have been disposed of as waste products from commercial stem cell manufacturing. We want to divert these discarded products and harness their therapeutic potential, Brennan says, This will make the whole stem cell manufacturing process more efficient and sustainable.

Remedi scientists have experience running patient cell therapy trials, with a trial to treat arthritis of the knee using patients own cells having finished and its results set to be reported during 2022. We dont have the formal results yet, but every piece of information that weve seen about this kind of effort suggests that there is a positive benefit associated with delivering cells to these arthritic joints, Barry says. The next step would be to conduct a larger, well controlled, multinational trial of the therapy, which could be led in Ireland.

There is a huge need for new therapies to treat bone defects, given that about 10 per cent of all bone fractures wont heal if left alone, while bone infection and surgery can leave big voids in bone that need to be healed. This is where new approaches based on EVs can come in, says Brennan. These tiny particles hold huge promise for regenerating not only bone tissue, but also older tissues and organs, and have healing potential in other diseases too.

A key challenge to sort out with EV-based therapies is to find a way to safely transport them from the stem cell manufacturing facility to the clinic. Brennan and her team are investigating ways to allow the vesicles to be stored for longer durations at room temperature. The ultimate goal is to develop novel EV treatments that are inexpensive and available off the shelf when a patient has an injured or damaged tissue or needs an anti-inflammatory treatment.

The whole idea about these technologies is that they are regenerative, stimulate repair or correct defects which are chronic, Barry notes. If they work then you are saving years and years of care associated with chronic illness. The economics of this make an awful lot of sense, and the investment that is needed is very much worth it in terms of the long term.

This is a huge new industry which is exploding worldwide and will require advanced manufacturing capacity in all corners of the world, Barry points out. There is an opportunity for Ireland to become a major centre of this, and we have the people, expertise, and infrastructure to allow the industry to develop here. We need to move with lightning speed to capture the opportunity.

The idea of Ireland becoming a global hub for cell and gene therapy and manufacturing is something we should talk about seriously, he adds.

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Tackling chronic disease with gene and cell therapies - The Irish Times

A University of Arizona Health Sciences study found that a specific genotype of the APOE gene, better known as the Alzheimers gene, is able to significantly influence metabolic changes and override sex-specific differences between men and women with Alzheimers disease.

The discovery may provide critical insights for personalized medicine related to late-onset Alzheimers disease, a complex neurodegenerative disease characterized by multiple progressive stages including cognitive decline.

One of the most interesting findings of our study is the identification of key drivers of metabolic pathways that discriminate between Alzheimers disease and cognitively normal individuals when patient groups were separated by sex and APOE genotype, said Rui Chang, PhD, a member of the University of Arizona Health Sciences Center for Innovation in Brain Science and lead author of the study. These patient-specific metabolic targets will shed light on the discovery of precision therapeutics for Alzheimers patients, which has not been done in previous studies.

The paper, Predictive metabolic networks reveal sex and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimers Disease, was published today in Alzheimers and Dementia: The Journal of the Alzheimers Association.

The APOE gene is involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream. There are several genotypes, or variations, of APOE based on the specific gene variants an individual inherits. The APOEe4 genotype has been identified as a risk factor for Alzheimers disease.

Dr. Chang and the research team integrated a metabolic network model with advanced machine learning approaches to perform a computational analysis on 1,517 serum samples provided by the Alzheimers Disease Neuroimaging Initiative.

First, they identified common metabolic signatures of late-onset Alzheimers disease. Next, they separated the network into clusters by sex to identify sex-specific metabolic changes and by genotype to identify other metabolic signatures influenced by the APOEe4 genotype.

Finally, they stratified patients by intersection of sex and APOEe4 status together and found that the APOEe4 genotype was able to significantly influence metabolic changes while overriding sex-specific differences in males and females.

Additionally, they identified serum-based metabolic biomarker panels that are predictive of disease state and associated with clinical cognitive function for each of the eight patient subgroups stratified by sex and/or APOEe4 status.

These novel patient-specific metabolic panels identify key metabolic drivers of late-onset Alzheimers disease that could be evaluated as therapeutic targets. The findings have the potential to greatly accelerate drug development for Alzheimers disease while providing outcome measures for clinical trials.

"Dr. Changs research provides an initial but critical step toward the development of personalized and precision medicine for Alzheimers disease, said Roberta Diaz Brinton, PhD, Regents Professor of Pharmacology and director of the Center for Innovation in Brain Science. This study provides an operational strategy to achieve that goal by integrating clinical cognitive assessments, metabolic profiling and a computational network model to identify targeted therapeutics for patients.

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Study Identifies Biomarkers that Could Guide Precision Medicine Therapies for Alzheimer's Disease - University of Arizona

CAMBRIDGE, Mass., April 27, 2022 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, will report first quarter 2022 financial results after the Nasdaq Global Market closes on Wednesday, May 4, 2022. Subsequently, at 4:30 p.m. E.T., the Company will host a conference call to discuss its first quarter 2022 financial results and to provide a corporate update.

The conference call may be accessed by dialing (800) 895-3361 for domestic callers and (785) 424-1062 for international callers. The passcode for the call is SAREPTA. Please specify to the operator that you would like to join the "Sarepta Therapeutics First Quarter 2022 Earnings Call." The conference call will be webcast live under the investor relations section of Sarepta.com and will be archived there following the call for 90 days. Please connect to Sarepta's website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary.

About Sarepta TherapeuticsSarepta is on an urgent mission: engineer precision genetic medicine for rare diseases that devastate lives and cut futures short. We hold leadership positions in Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophies (LGMDs), and we currently have more than 40 programs in various stages of development. Our vast pipeline is driven by our multi-platform Precision Genetic Medicine Engine in gene therapy, RNA and gene editing. For more information, please visitwww.sarepta.com or follow us on Twitter, LinkedIn, Instagram and Facebook.

Internet Posting of InformationWe routinely post information that may be important to investors in the 'For Investors' section of our website atwww.sarepta.com. We encourage investors and potential investors to consult our website regularly for important information about us.

Source: Sarepta Therapeutics, Inc.

Investor Contact: Ian Estepan, 617-274-4052iestepan@sarepta.com

Media Contact: Tracy Sorrentino, 617-301-8566tsorrentino@sarepta.com

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Sarepta Therapeutics to Announce First Quarter 2022 Financial Results and Recent Corporate Developments on May 4, 2022 | Sarepta Therapeutics, Inc. -...

Holly Tabor

Associate professor, Stanford University

For many people with a genetic condition, uncovering the gene responsible opens the door to accurate diagnosis and better treatment. But thats not yet the case for most autistic people despite decades of research that has implicated hundreds of genes.

The disconnect raises ethical questions about the goals and practice of autism genetics research, says Holly Tabor, associate professor of medicine at Stanford University in California and associate director for the schools Center for Biomedical Ethics.

Most autism genetics studies tout the possibility of more personalized treatments following a genetic diagnosis, but with such treatments not yet a reality, scientists need to reconsider their stated goals, Tabor says. Not getting it right can have big consequences. In October, for example, researchers had to pause recruitment for the U.K. genetics study Spectrum 10K after some autistic advocates questioned that studys aims.

That doesnt mean we stop doing the research or the research is inherently bad, says Tabor, whose son is autistic. Its more about, how can we do it better? How do we not have another 20 years of research that doesnt significantly impact the lives of people with autism?

Tabor spoke with Spectrum about autism researchers social responsibilities, the ableism that, in her opinion, permeates the genetics field, and the need for that community to reflect on its future.

This interview has been edited for length and clarity.

Spectrum: What issues do you see in autism genetics research?

Holly Tabor: I have been really disheartened and disappointed at the lack of tangible outcomes that have come from a tremendous amount of excellent genomic research over the past 20 years. I dont think that thats anybodys fault. That was the right thing to do, and it continues to be a good research thing to do. But we have to be honest about the real outcomes and the ways in which we havent actually succeeded as we hoped. Transparency is important if we want to continue doing this research.

In research on other genetic conditions, such as cystic fibrosis or sickle cell disease, the people doing genetic research overlap with people involved in clinical care and diagnosis. In autism, historically theres been more of a divide. That leads to a gap in the agenda for the research. That is really an opportunity to be filled, and an opportunity for funding agencies to target. It doesnt mean we shouldnt do genetic research, but we should make it more integrated with the community and with the needs of the community.

I like the Maya Angelou quote: When you know better, do better. We know better, and we can do better.

S: How can geneticists better integrate the autistic community in their work?

HT: One way is by building on some of the models from PCORI [Patient-Centered Outcomes Research Institute] and other kinds of community-based participatory research to involve adults with autism to set the agenda, design the research and think about the translation of the research. Theres a science of how to do this properly. There are some protocols that have been empirically tested about how to engage communities properly. That would really help with challenges such as what happened with Spectrum10K.

Theres also a real opportunity to think about other ways that genetics and genomics research can be implemented into clinical care and diagnosis. If we found more genetic loci that predispose people to autism, what would we do with that information? Part of the dream for many researchers is to be able to say, People with this genetic susceptibility gene are more likely to respond to this kind of therapy, or to have challenges with speech and communication.

We need to think bigger than that. We have these cohorts with some clinical data and a lot of genetic data. What other kinds of questions can we study about the natural history of autism, about the lived experiences of people with autism, about different kinds of interventions? How can we involve the communities in that research to be dynamic partnerships? Whats the sustainability? How are we going to build on the data collections?

S: Ive heard you say that autism genetics researchers have a responsibility to be leaders in ethical genetics research, given how big the datasets are. What does that responsibility look like?

HT: The scientific, social, anthropological structure on which most science is based emphasizes people being experts in one particular discipline. And there arent a lot of incentives to have people think about their social responsibility. What are the injustices that still exist for people with the condition or people in the specific population that Im studying? How can I involve people in my work to become more aware of that? How can I partner with other researchers who have different expertise?

I would love to see funding agencies incentivize collaboration and partnership with the community of people with autism and their families, to try to have some shared values and priorities. You could argue that the Interagency Autism Coordinating Committee sort of does that. But it doesnt trickle down to the individual researchers.

Theres also a legitimate criticism among autistic people that genetics research is primarily not designed for them, and that its not going to improve their life. Its really hard to argue with that.

Some of the same people will argue that the kind of genetics and genomics research that has historically happened with autism, and is still happening, is really designed to try to make sure that people with autism arent born. I was at an ethics and autism conference a number of years ago, and someone asked me why I wanted to support genetics research and was I a eugenicist. I was really taken aback. I had always seen, and still do see, genetics for the power it can have to improve peoples lives. But it was a pivotal moment for me in thinking about the reasons why many people with autism perceive autism genetics research this way. Autistic people are more studied than they are partners in studies. Thats wrong.

S: Do you think ethics education could help?

HT: I dont think that thats the main solution for autism. What I would love is to have a component of the funding mechanism require engagement with the autistic community. I would like conferences and forums to bring in autistic people along with people who do autism research in genetics and genomics and in totally different areas. This includes conferences that are not autism specific but might have autism genomics research being presented, such as the American Society of Human Genetics or the American College of Medical Genetics meetings.

As a field, we have to be more aware about the context of autism and disability. Autism is very much a target of the medical model of disability. The approach has been, If we could only figure out the causes of autism, then we could prevent it, we could treat it, we could fix it. And there are some things about that that are not wrong. But it also contains a significant component of ableism that autism is such a tragedy. Thats dangerous and, quite frankly, inappropriate.

Moving forward, Im hoping for clinical genomics in general, and autism clinical genomics specifically, to have an anti-ableist view of thinking that doesnt minimize the legitimate quality-of-life issues and medical issues that exist for people with autism, particularly for people with more severe manifestations, but that also doesnt treat it as something we have to fix that were going to have a widely applicable gene therapy for someday.

Cite this article: https://doi.org/10.53053/RTOW6991

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Ethical gaps in autism genetics: A conversation with Holly Tabor | Spectrum - Spectrum

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