In support of this year’s Rare Disease Day, the global movement on rare diseases which works towards equity in social opportunity, healthcare, and the provision of diagnostics and therapies for individuals living with rare diseases, we talk to Alex Silver, co-founder of Telaria, Replay’s HSV gene therapy product company targeting rare skin diseases. 

After their son Jackson was born and diagnosed with recessive dystrophic epidermolysis bullosa (RDEB), Alex and his wife started a foundation which grew into the EB Research Partnership; the largest global organization dedicated to funding research to treat and cure epidermolysis bullosa (EB). 

EB comprises a group of devastating and life-threatening skin disorders affecting children from birth and that makes the skin as delicate as a butterfly's wings. There's currently no cure, so treatments aim to relieve symptoms, reduce pain, and prevent complications, such as infection. The genetic skin disease gene therapy field is advancing research intent on bringing a substantive change to how EB is treated. 

__You’ve been actively involved in funding and driving research into epidermolysis bullosa (EB) for more than a decade. How has the field changed in that time?__

When my fifteen-year-old son was born with recessive dystrophic epidermolysis bullosa (RDEB), there were very few active clinical trials. The disease-modifying trials were highly risky and uncertain in the benefit that could be delivered. Furthermore, gene therapies were much more of a fantasy than a reality. While there is still no disease-modifying therapy approved for EB, the progress over the last 15 years has been tremendous. The number of potential therapies and modalities gives me great hope that a life-changing treatment or potential cure is on the horizon. As the parent of a child living with EB, this can't come fast enough. I am encouraged by the amount of people, companies, and investors working together to create this outcome. 

__You established the Epidermolysis Bullosa Research Partnership, which went on to be the largest global organization dedicated to funding research to treat and cure EB. What drove you?__

My son has been my motivation since the day he was born. My wife and I were fortunate to have great medical care, but nothing could have prepared us for his diagnosis. After a routine heel prick to test blood sugar because my wife had gestational diabetes, the nurses placed a Band-Aid on his foot that took off all the skin when it was removed. That was the moment that I decided to do whatever I could to help him. We started a non-profit at our kitchen table that I chaired until mid-2022. We grew that from nothing to raising over $55 million, funding over 85 projects and supporting more than 30 clinical trials, mostly via a venture philanthropy model that I created. As my son's condition has advanced – along with my knowledge of how to get commercially sustainable treatments to the finish line – I have reallocated my time towards the most life-changing and commercially viable possibilities out there.  I am not alone in saying that as an EB parent, I live in awe of my child's strength, and I am inspired every day by him.

__How has the advent of gene therapy changed the EB research field?__

Approximately 12 years ago, I was at a leading academic institution that was pioneering a gene therapy for EB. The timeline being discussed was 20+ years out.  Yet here we are with gene therapies in or near clinical trial stages! That's amazing. The benefit of gene therapy is that it treats the root cause of the problem. What many people don't realize is that skin is your largest organ, and first line of defense. Everything you do in life impacts your skin – sleeping, waking, and even sitting. In addition, EB really is a connective tissue disorder. The same protein that impacts skin integrity is in your eyes, throat, and GI tract. The people living with EB have a systemic condition. By fixing the gene that causes EB, the therapy should help all the downstream effects of EB such as inflammation, infection, etc. Let's also keep in perspective that there are an estimated 7,000 rare diseases that impact 10% of our population. That is 32-33 million people! Gene therapy is a platform technology. If you can show that it works in EB then you can likely have it work in other rare conditions. In other words, gene therapy success in EB bodes well for the thousands of other rare genetic conditions that exist without treatments.

__What are some of the biggest challenges you’ve had to overcome in your EB journey so far?__ 

The greatest challenge for me has been the timeline to an approved life-changing treatment. By that I mean, we established a foundation and drove clinical trials, created a biotech, and advocated for funding in front of the US Senate. I have no doubt that our efforts have helped advance EB therapies and changed the landscape in a positive way. Developing approved, life-changing treatments takes time, and time is something that someone living with a rare disease values the most. I am optimistic though that we are closer to therapies that will really change the lives of those living with EB. When we started our foundation, there were some wonderful supporters, and also some with the view that we couldn't impact the lives of those living with EB because it was too hard to drive change. Looking back now, I can draw a line to almost every single late-stage therapy in clinical trial and our funding of it. That gives me solace, as even if we aren't there yet, we are well on the way.

__Given what you know today, compared to when Jackson was born, what advice would you give to a new parent of a child living with EB?__ 

This is a hard question to answer as every child with EB has a unique journey. I think the best advice that I can offer is to try as hard as possible to live in the present and not fantasize about the life that you imagined you would have had as a parent. Nobody believes that his or her child will be born with a rare disease, and there are some very, very hard days. We each have one trip on this earth and, as hard as it has been for my son quite often, I consider myself among the luckiest of people to have him in my life. 


Portraits Alex Silver Green Background

Rare Disease Day 2023: In conversation with Alex Silver 


- Cord blood-derived T-Cell Receptor Natural Killer (TCR-NK) platform offers potential for scalable off-the-shelf cell therapy 
- Syena co-founded by Professor Katy Rezvani, M.D., Ph.D., an oncologist and pioneer of engineered NK cell therapy
- Phase 1 study in solid tumors and hematological malignancies anticipated to commence in Q2 2023 

__San Diego, California, London, UK, and HOUSTON, February 14, 2023__ – Replay, a genome writing company reprogramming biology by writing and delivering big DNA, and The University of Texas MD Anderson Cancer Center, today announced the launch of Syena, a new oncology-focused product company pioneering T-cell receptor (TCR) natural killer (NK) cell therapies (TCR-NKs). 

Building on the intellectual property and technology from MD Anderson and Replay, Syena has the potential to create the next generation of cell therapy, combining the safety, potency, and scalability of NK cells with the ability of TCRs to target intracellular tumor antigens. The new company’s TCR-NK cell platform is based upon the scientific discoveries of Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation & Cellular Therapy at MD Anderson. 

“This first-in-class TCR-NK technology provides an opportunity for Replay to disrupt the existing cell therapy paradigm and positions Syena to become a leader in this space,” said __Adrian Woolfson, Executive Chairman, President, and Co-Founder of Replay__. “While clinical successes in hematological malignancies have demonstrated the transformative potential of engineered cell therapies, these successes have not yet been realized in solid tumors. NK cells offer distinct advantages over T-cells and building on Dr. Rezvani’s research to arm them with TCRs has the potential to significantly impact oncology cell therapy.” 

Based on the contributions of Replay and MD Anderson, Syena will build a pipeline of engineered cell therapies using its novel TCR-NK cell platform, licensed exclusively from MD Anderson. It is targeting a selection of validated cancer neoantigens, including NY-ESO-1, and additional undisclosed TCRs. The NY-ESO-1 program in hematological malignancies and solid tumors is anticipated to enter the clinic in Q2 2023.

Syena’s TCR-NK cell therapy platform will combine the advantages of engineered TCR cancer therapy with those of NK cells, offering the possibility of improved safety and efficacy through a multi-armored approach incorporating natural and artificial mechanisms. Unlike chimeric antigen receptor (CAR)-based therapies, which recognize specific surface proteins, TCR therapies are engineered to recognize proteins normally found inside the cell. The use of a TCR allows the NK cell to recognize externalized protein fragments presented by the cell’s surface immune proteins. 

“NK cells play a pivotal role in anticancer immunity and, following the successes of CAR T-cell therapy, and the potential for CAR-NK therapies, TCR-NK cells are positioned to be a next-generation agent for cancer therapy,” said __Dr. Katy Rezvani__. “We believe that the TCR-NK cell approach will allow targeting of a broad range of tumor antigens, including cancer-specific neoantigens, and could pave the way for potentially safe and efficacious ‘off-the-shelf’ cell therapies for hematological malignancies and solid tumors.”

Rezvani’s work at MD Anderson has explored the role of NK cells in mediating innate immunological activity against human malignancies, as well as strategies to enhance their killing function. She was the first investigator to conduct a clinical trial with cord blood derived CAR-NK cells (Liu et al, NEJM 2020), and has successfully advanced 11 cell therapies into the clinic through MD Anderson’s institutional support and commitment to advance innovative science. 

“We are delighted to have Dr. Rezvani, a world-leading expert in NK-based cell therapy and pioneer of CAR-NK cell therapy, as the scientific founder of Syena,” said __Lachlan MacKinnon, CEO and Co-Founder of Replay__. “Dr. Rezvani has generated compelling clinical data with CAR-NK cell therapies, and her expertise with engineered NK cells will prove invaluable in guiding our scientific efforts. We believe Syena has the potential to redefine this emerging area of medicine and to provide compelling new cell therapy options for patients in need.”

Syena will receive licenses to various Replay cell and genome engineering platform technologies.

“MD Anderson and Dr. Rezvani have advanced outstanding science in this space, and we look forward to working with them to accelerate the development of these novel cell therapies,” said __Kugan Sathiyanandarajah, Managing Director at KKR and a Board Director at Replay__. “Coupled with Replay’s platform technologies and oncology drug development experience, Syena has the potential to have a significant impact on this important life science sector and to make a meaningful contribution to human health.”

__Ends__

__Disclosure__

MD Anderson has an institutional conflict of interest with Replay and Syena, and these relationships will be managed according to an MD Anderson Institutional Conflict of Interest Management and Monitoring Plan.

__About Replay__

Replay is a genome writing company, which aims to define the future of genomic medicine through reprogramming biology by writing and delivering big DNA. The Company has assembled a toolkit of disruptive platform technologies – including a high payload capacity HSV platform, a hypoimmunogenic platform, and a genome writing platform – to address the scientific challenges currently limiting clinical progress and preventing genomic medicine from realizing its full potential. The Company’s hub-and-spoke business model separates technology development within Replay from therapeutic development in product companies, which leverage the technology platforms. For example, Replay’s synHSV™ technology, a high payload capacity HSV vector capable of delivering up to 30 times the payload of AAV, is utilized by Replay’s four gene therapy product companies, bringing big DNA treatments to diseases affecting the skin, eye, brain, and muscle. The Company has, additionally, established an enzyme writing product company engaging its evolutionary inference machine learning and genome writing technology to optimize functionality. Replay is led by a world-class team of academics, entrepreneurs and industry experts. 

The Company raised $55 million in seed financing in July 2022 and is supported by an international syndicate of investors that includes KKR, OMX Ventures, ARTIS Ventures, and Lansdowne Partners.

Replay is headquartered in San Diego, California, and London, UK. For further information please visit https://replay.bio/ www.replay.bio and follow us on LinkedIn and Twitter.  

__About The University of Texas MD Anderson Cancer Center__

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. The institution’s sole mission is to end cancer for patients and their families around the world. MD Anderson is one of only 53 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is No. 1 for cancer in U.S. News & World Report’s “Best Hospitals” rankings and has been named one of the nation’s top two hospitals for cancer since the rankings began in 1990. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672). 

__Contacts:__

__Replay__

Dr Adrian Woolfson/Lachlan MacKinnon
info@replay.bio

__Consilium Strategic Communications – Media relations__

Amber Fennell/Tracy Cheung/Melissa Gardiner
replay@consilium-comms.com

__MD Anderson__

Clayton Boldt, Ph.D.
CRBoldt@MDAnderson.org


KKR-backed Replay and MD Anderson form new product company Syena to pioneer first-in-class TCR-NK cell therapy 

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31 Katy Rezvani light green

Replay Bio partners with MD Anderson’s Katy Rezvani, heads to clinic with new TCR NK cell company


- Third product company from Replay expands use of next-generation high payload capacity HSV delivery vector developed at the University of Pittsburgh by Kaleibe co-founder Professor Joe Glorioso into brain indications
- Experts in neuroscience and neurology, Professors Richard Wade-Martins and Howard J Federoff, also co-founders of Kaleibe
- Initial programs to target genetic Parkinson’s disease and Friedreich’s ataxia

__San Diego, California and London, UK, December 13, 2022__ – Replay, a genome writing company reprogramming biology by writing and delivering big DNA, today announced the launch of Kaleibe, an HSV gene therapy company targeting genetic brain disorders. It is the third of Replay’s product companies to launch since the Company’s formation in July and will leverage Replay’s high payload capacity herpes simplex virus (HSV) delivery vector, synHSV™, to target genetic brain disorders.

Kaleibe’s co-founders include distinguished Professors Richard Wade-Martins, whose research at the University of Oxford focuses on the molecular mechanisms underlying neurodegenerative diseases, and Howard J Federoff, former distinguished Professor of Neurology at University of California, Irvine, and formerly CEO at regenerative medicine company, Aspen Neuroscience, Inc. Professor Joe Glorioso, the inventor of synHSV™, is also a co-founder of Kaleibe. 

The initial development programs will focus on genetic Parkinson’s disease (PD) and Friedreich’s ataxia (FRDA). These diseases have a high unmet medical need and known genetic causes. The target genes, 33kb and 135kb, respectively, far exceed the payload capacity of adeno-associated virus (AAV) vectors (5kb). Affecting more than 6 million people worldwide, PD is the most prevalent movement disorder and second most common neurodegenerative disorder globally, after Alzheimer’s disease. It is estimated that approximately 15 per cent of cases are inherited, with a loss of functional genes that can be targeted by genomic medicines. FRDA is a genetic, progressive, neurodegenerative movement disorder affecting around 1 in every 50,000 individuals, with a typical age of onset between 10 and 15 years. It leads to impaired muscle coordination (ataxia) that progresses over time. Treatment options are limited and involve managing the symptoms and complications of the disorder.

The launch of Kaleibe follows the launches of product companies Eudora and Telaria focused, respectively, on diseases of the eye and skin. Replay’s distinctive corporate structure separates technology development from product development within disease therapeutic area-focused product companies.

__Adrian Woolfson, Executive Chairman, President and Co-Founder of Replay__, said: “HSV’s natural neurotropism allows the virus to establish a latent infection in neurones and enables robust transgene expression across multiple brain regions. It was therefore rational for us to apply our proprietary delivery platform, synHSV™, to target genetic disorders of the brain, where we believe HSV offers the promise of gene delivery that is safer and more durable than AAV-based approaches. The high payload capacity of HSV, furthermore, allows for the expression of genomic genes, thereby deploying natural regulatory sequences and capturing alterative splice forms.”

__Lachlan MacKinnon, CEO and Co-Founder of Replay__, said: “The launch of Replay’s third product company highlights the strength and broad applicability of our synHSV™ technology, as well as our ability to leverage its payload capacity by delivering cassettes of up to 150kb in length. With Kaleibe, we are fortunate in having leading neuroscience and clinical neuroscience and neurology experts as co-founders, leveraging synHSV™ to bring novel treatments to patients with debilitating brain disorders.”

__Professor Richard Wade-Martins, Co-Founder of Kaleibe__, said: “Replay’s mission to write and deliver big DNA resonates with my own research interest in this area. Genetic Parkinson’s disease and Friedreich’s ataxia are diseases characterized by mutations in particularly sizeable genes, making them especially difficult targets for AAV-based gene therapies. With the potential to deliver up to 30x the payload of AAV, Replay’s synHSV™ platform facilitates the delivery of large genes – so called ‘big DNA’ – with the promise of a differentiated and compelling therapeutic option for these, to date, intractable disorders.”

__Professor Howard J Federoff, Co-Founder of Kaleibe__, said: “Kaleibe aims to illuminate genetic brain disorders that have a high unmet medical need and that are associated with a significant detrimental impact on the quality of life of patients. Replay’s differentiated approach brings together the necessary elements to position the Company for success. I look forward to working with the team to leverage Replay’s synHSV™ technology platform to develop novel treatments addressing genetic mechanisms beyond the reach of other technologies that have the potential to have a significant and durable clinical impact.”

__Professor Joe Glorioso, Co-Founder of Kaleibe__, said: “Our next-generation HSV delivery platform has several distinct advantages over, and has the potential to be disruptive to existing gene delivery platforms. The defined genetic causes of the neurological disorders under investigation at Kaleibe provide us with the opportunity to introduce profound and long overdue technological innovation into the treatment landscape.”

__About the Kaleibe team__

__Professor Richard Wade-Martins__ is a Co-Founder of Kaleibe. He graduated from Cambridge in Natural Sciences taking Part II Genetics in 1995. He then moved to the Wellcome Trust Centre for Human Genetics in Oxford for a DPhil followed by a Wellcome Trust Fellowship. In 2000 Richard moved to Massachusetts General Hospital, Harvard Medical School as a Wellcome Trust Travelling Research Fellow. He returned to Oxford and in 2004 was awarded a Wellcome Trust Research Career Development Fellowship and started his own group. In 2007 he moved to the Department of Physiology, Anatomy and Genetics, University of Oxford, as a University Lecturer. Richard gained tenure in his faculty position in the University of Oxford in 2013, was appointed an Associate Professor in 2014 and Professor in 2015. His research is focused on  the molecular mechanisms underlying neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease. It combines studies on human post-mortem brain tissue, the generation and analysis of novel transgenic and knockout mouse models, and the development of improved induced pluripotent stem cell (iPS) derived dopaminergic neuronal culture models. His work focuses on the study of the functional and genetic mechanisms underlying key neurodegeneration disease loci, including alpha-synuclein (SNCA), microtubule associated protein tau (MAPT), and leucine rich repeat kinase 2 (LRRK2).

__Professor Howard J Federoff, MD, PhD__, is a Co-Founder of Kaleibe. He is former distinguished professor of neurology at the University of California, Irvine. He is the former CEO of UCI Health, vice chancellor for Health Affairs and dean of the UCI School of Medicine. Prior to joining UCI Health, Federoff was Executive Vice President of Health Sciences and executive dean at Georgetown University. Federoff has published more than 275 peer-reviewed and invited articles and serves on editorial boards of five journals. He co-founded MedGenesis Therapeutix and Brain Neurotherapy Bio, both advancing therapeutics for neurologic diseases. He became CEO of the regenerative medicine company, Aspen Neuroscience, Inc, in San Diego. Aspen is developing an autologous iPSC drug product for Parkinson’s disease. Federoff chaired the NIH Recombinant DNA Advisory Committee, the NHLBI Gene Therapy Resource and the Board of the Association of the Academic Health Centers. He has served as an advisor/director for several companies. He is an elected Fellow of the American Association for the Advancement of Science and the National Academy of Inventors. He received his MD, MS and PhD in biochemistry from the Albert Einstein College of Medicine in New York. He completed his residency and clinical and research fellowships at Massachusetts General Hospital and Harvard Medical School.

__Professor Joe Glorioso, PhD__, is the Senior Advisor on synHSV™ at Replay and Co-Founder of Kaleibe. He is the former Chair and a Professor in the Department of Microbiology and Molecular Genetics at the University of Pittsburgh School of Medicine and holds a secondary appointment in the Department of Human Genetics, University of Pittsburgh Graduate School of Public Health. He has a 40-year history of research related to the basic immunobiology, genetics and pathogenesis of herpes simplex virus (HSV). He has pioneered the design and application of HSV gene vectors for the treatment of nervous system diseases such as peripheral neuropathies, chronic pain, and brain tumors, and has developed manufacturing methods for human clinical trials. Professor Glorioso was a Founding Board Member and former president of the American Society of Gene Therapy, and is an elected fellow of the American Society for Microbiology, the American Association for the Advancement of Science and the National Academy of Inventors. Professor Glorioso is a founding member of the International Society for Neurovirology and an active member of the American Society for Virology, Society of Neurooncology, the International Pain Society, and American Society of Cancer Research.

__Ends__

__About Kaleibe__

Kaleibe is Replay’s third gene therapy product company and is focused on genetic brain disorders. The company’s next-generation HSV-1 technology was licensed from the University of Pittsburgh, where it was developed by leading HSV specialist and entrepreneur Professor Joe Glorioso. Kaleibe’s co-founders include Professors and experts in neurology, Richard Wade-Martins and Howard J Federoff.

__About Replay__

Replay is a genome writing company, which aims to define the future of genomic medicine through reprogramming biology by writing and delivering big DNA. The Company has assembled a toolkit of disruptive platform technologies – including a high payload capacity HSV platform, a hypoimmunogenic platform, and a genome writing platform – to address the scientific challenges currently limiting clinical progress and preventing genomic medicine from realizing its full potential. The Company’s hub-and-spoke business model separates technology development within Replay from therapeutic development in product companies, which leverage the technology platforms. For example, Replay’s synHSV™ technology, a high payload capacity HSV vector capable of delivering up to 30 times the payload of AAV, is utilized by Replay’s four gene therapy product companies, bringing big DNA treatments to diseases affecting the skin, eye, brain, and muscle. The Company has, additionally, established an enzyme writing product company engaging its evolutionary inference machine learning and genome writing technology to optimize functionality. Replay is led by a world-class team of academics, entrepreneurs and industry experts. 

The Company raised $55 million in seed financing in July 2022 and is supported by an international syndicate of investors that includes KKR, OMX Ventures, ARTIS Ventures, and Lansdowne Partners. 

Replay is headquartered in San Diego, California, and London, UK. For further information please visit  www.replay.bio and follow us on LinkedIn and Twitter.  

__Contacts:__

__Replay__

Dr Adrian Woolfson/Lachlan MacKinnon
info@replay.bio

__Consilium Strategic Communications – Media relations__

Amber Fennell/Tracy Cheung/Melissa Gardiner
replay@consilium-comms.com


Replay targets genetic brain disorders with new gene therapy company, Kaleibe, utilising big DNA HSV technology

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Writing Genes

- Rapid and cost-effective gene synthesis 
- Synthetic gene library generation 
- Rewrite and optimise gene sequences


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- Write and deliver big genes, genomic genes, and multiple genes 
- Complex regulatory elements and synbio circuitry
- Multiplex transcription factors in conjunction with control elements
- Polygenic medicine

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- Deliver big DNA to autologous, allogeneic, and iPSC-derived cell therapies
- Write and install large constructs to replace multiplex editing 
- Enable extensively genomically rewritten iPSC-derived therapies
- Regenerative medicine, CARs, TCRs
- Multiple cell types 

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- Mini Y chromosome (Human Y : 57mb) 

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- Synthetic human chromosomes for iPSC-derived cell therapy
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Reprogramming biology by writing and delivering big DNA

Latest news

Rare Disease Day 2023: In conversation with Alex Silver

KKR-backed Replay and MD Anderson form new product company Syena to pioneer first-in-class TCR-NK cell therapy

Replay Bio partners with MD Anderson’s Katy Rezvani, heads to clinic with new TCR NK cell company

Replay targets genetic brain disorders with new gene therapy company, Kaleibe, utilising big DNA HSV technology