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2022/08/11

Delivering on the Promise of New Modalities: An Interview with Yann Chong Tan, Founder & CEO, Nuevocor

As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs. We continue our interview series with Yann Chong Tan, Founder & CEO of Nuevocor, a preclinical-stage biotech company specializing in gene therapy for cardiomyopathies. Recently, Nuevocor closed on $24 million Series A Financing to advance their novel gene therapies. The company believes they are well-positioned to treatLMNA (lamin A/C gene) and other genetic cardiomyopathies, amongst other cardiac diseases. Nuevocor focuses on developing gene therapy-based treatments that have the potential to restore cardiac function in diseased hearts. In your opinion, what are the top challenges in current therapeutic intervention for this disease? Yann Chong: At Nuevocor, we focus on using gene therapy to treat genetic cardiomyopathies. Cardiomyopathy is estimated to affect more than 1 in 250 people and is a disease where the heart gradually loses its ability to pump blood efficiently. Treatment options are limited and the only cure is a heart transplant. With the advent of precision medicine over the past decades, we now know that a large fraction of cardiomyopathies has genetic causes. As each of these genetic cardiomyopathies has a different mechanistic driver, a challenge is understanding the underlying root causes to design targeted treatments. How is your gene therapy approach helping to address these challenges? How is it different from existing approaches? Yann Chong: The majority of genetic cardiomyopathies are inherited in an autosomal dominant manner where one copy of the mutated gene drives the disease even though the patient has a second, normal copy of the gene. This makes a gene replacement approach unworkable. There are also no mutation hotspots for gene editing to be attractive. Our approach is to identify genetic modifiers of cardiomyopathies and deliver them to patients via AAV-mediated gene therapy. To identify such genetic modifiers as therapeutic targets for genetic cardiomyopathies, we utilize our PrOSIA mechanobiology platform to understand the molecular and biomechanical basis of genetic cardiac disease. To illustrate the power of our approach, our lead programme targets LMNA dilated cardiomyopathy. This is the second most common genetic dilated cardiomyopathy and has the worst prognosis, with 70% of patients having cardiac death, a heart transplant or a major cardiac event by the age of 45. Our treatment reduces biomechanical stress on the nucleus of LMNA mutant heart cells, thereby reducing nuclear damage in LMNA dilated cardiomyopathy. In animal models, we have extended lifespan by more than 4-fold with our approach, which is unprecedented for this rare disease. What are critical challenges in realizing the full potential of your gene threapy? What are Nuevocor’s solutions? Yann Chong: The benefits of AAV-mediated gene therapy have been demonstrated with drug approvals and have made a significant difference in patients’ lives. Recent clinical trials, however, have highlighted that there are still quite some ways to go in ensuring that the therapy is safe for patients especially at high doses. The field is coming together to solve these issues and there has been incredible progress in understanding the cause of the safety challenges and in designing solutions. We are actively working on addressing these safety challenges by examining how we can lower the AAV dose and ensuring that our therapeutic protein is not immunogenic. We have made significant progress in the past year and we are confident that we will be able to have a solution in the coming year. To make a prediction, what could be the next big scientific breakthrough in the life science industry? Yann Chong: It is difficult to predict the next big invention, but what is clear is that techniques regularly used in research to perturb systems and answer biological questions, such as anti-sense oligos, or mRNA and DNA vectors for expressing and regulating genes, have formed the basis for new drugs in recent years. There is no turning back from these new nucleic acid therapeutic modalities, which promise to address the root cause of diseases so as to provide cures for patients. Enabling wider use of these technologies is in the interest of patients and their families. A challenge for these modalities is delivering the therapeutic molecule to the intended cell types, ideally with good specificity and importantly, also in a way that is safe. We expect current delivery methods to mature, and at the same time, a proliferation of different delivery methods, both viral and non-viral. It is likely that each delivery method will have its own advantage in being able to deliver well to different organs and cell types. We anticipate the next breakthrough to be the ability of the field to deliver to different cell types achieved through the coexistence of multiple viral and non-viral delivery technologies. Thank you for your insights! Any closing remarks to our readers? Yann Chong: We believe in moving our therapies as quickly as possible into the clinic, and collaborations between different groups with complementary capabilities can accelerate the process. Capabilities do not respect borders and ideally collaborations should be cross-border too. Nuevocor is headquartered in Singapore, a cosmopolitan global city with English as the main communication and is in many ways a bridge between Asia and the West. It should come as no surprise that we already have global collaborations with our strong ties to North America, Europe and Asia. We are always actively seeking more collaborations to move the science forward.     Yann Chong Tan Founder & CEO, Nuevocor Yann Chong Tan, PhD, brings a decade of experience in biotech and commercialisation leadership roles to Nuevocor. He is an inventor on multiple patents and an entrepreneur who has founded multiple biotech companies. Dr. Tan was previously the Chief Innovation Officer at the Genome Institute of Singapore, where he initiated and led strategic programmes resulting in multiple healthcare and biotech spin-offs, one of which is Nuevocor. Previously, as Chief Technologist at Atreca, Inc., a company he co-founded in 2012 from his academic work, Dr. Tan led and built up Atreca’s core foundational antibody discovery technology and discovered the antibody now in clinical trials. Atreca is listed on NASDAQ.

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2022/08/11

Delivering on the Promise of New Modalities: An Interview with George Wu, Co-Founder & CEO, Amberstone Biosciences

As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs. For our next interview as part of our featured series highlighting innovation in our ecosystem, we sat down with George Wu, Co-Founder & CEO of Amberstone Biosciences, an emerging biotech company with expertise in developing a new generation of ‘conditionally active’ cancer therapies. Earlier this year, Amberstone Biosciences secured $12 million in Series A Financing to advance the immuno-oncology pipeline of tumor microenvironment activated therapeutics. The company also recently announced the formation of a scientific advisory board comprised of industry leaders in the top fields of drug delivery, oncology, immunology, and pharmaceutical sciences. Greetings George. Amberstone focuses on developing novel immuno-oncology therapeutics. In your opinion, what are the top challenges in current therapeutic intervention for cancer?? George: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, showing great clinical and commercial successes. But the majority of cancer patients don’t respond well to this class of treatments. There are still significant unmet medical needs for cancer patients. In search of novel cancer immune therapies, the field has encountered a major hurdle. Many potentially transformative new immunotherapeutics exhibit a very narrow therapeutic window, making them intractable for further development. Reducing the dose-limiting toxicities while maintaining efficacy of those promising agents is one of the biggest industrial-wide challenges. Inadequate tumor selectivity, poor adaptability to the heterogeneous patient immune systems, and suboptimal preclinical translational efficiency are some of key underlying gaps that the field endeavors to address in order to increase the chance of success. Another major challenge is the alarmingly high cost that has been limiting the upside potential of some innovative treatments such as cell-based therapeutics. It also limits patient access to those novel and effective treatments. What is your unique technological approach helping to address these challenges? How is it different from existing approaches? George: Amberstone Biosciences has a singular focus on developing tumor microenvironment activated immunotherapeutics (T-MATEs). Our molecules are selectively activated in acidic tumor microenvironment but not in physiological normal tissues, thus offering a favorable expanded therapeutic window. Our rationale is based on the well-known tumor acidity, in part due to glycolytic metabolism, a near-universal cancer hallmark that has been established for about 100 years with the solid support of over 10,000 scientific research articles. Our two lead programs are T cell engagers that are uniquely designed to address large and diverse solid tumor patient populations. For the current stage, we only adopt clinically established modalities (e.g. antibodies and cytokines) that provide a clear path of development. We expect that our approach can be integrated with a variety of modalities to target many promising regulatory pathways around the tumor immunity cycle. We are excited with the potential of our approach and are firmly committed to our mission of delivering a next generation of safe and effective treatments to benefit those with devastating cancer. What are critical challenges in realizing the full potential of your new technologies? Could you share with us your solutions and your upcoming milestone? George: While the overall path of development is fairly clear for our T-MATE programs, there is a shortage of highly-relevant preclinical models that can allow us to efficiently characterize our molecules’ efficacy, safety, and pharmacokinetics, thereby translating effectively to clinical benefits. We are working with several academic and industrial partners to address these challenges. For the time being, we are taking rigorous and somewhat redundant approaches to improve the chance of successful translation. Despite these challenges, we are optimistic with our next milestone goals in IND-enabling studies starting later this year. With many new modalities advancing into the clinic and getting closer to patients, do you think the 2030 class of FDA new approvals may look similar or different from those today? George: I think there will be increasingly more new modalities being approved — multispecific antibodies, off-the-shelf cell therapies, cancer vaccines, TLR agonists, and innovative personalized medicines, just to name a few. I also expect to see the approval of many nuanced combination strategies that can innovatively leverage existing treatments and therapeutics of various modalities. One example is to combine two or three immune-modulating molecules to achieve a balanced yet durable tumor-selective immunity to annihilate all cancer cells in a safe and effective manner; another example is to combine a “right” regimen of chemotherapy with a “right” kind of immunotherapy in a synergistic manner to improve the clinical outcome. Do you think we as industry will be able to achieve 100+ new drug approvals at 50% of today’s cost by 2030? And in achieving so, do you foresee any major gaps to bridge? Or any upcoming breakthroughs that you are most excited about? George: I expect there will be significant improvement of productivity for at least some modalities, particularly cell therapy. I am generally optimistic about technological innovations which are arising regularly. On the other hand, the production cost reduction may or may not adequately translate to favorable pricing on the healthcare systems or the improved affordability to patients. This is intricately related to individual countries’ respective situations. Do you see novel data technologies, AI, or machine learning being used in the next couple of years? George: Absolutely. I am a big fan of information/data technologies which have started and will only accelerate to create direct impact. Take a look at the quick evolution of the AlphaFold, as an example. There is no doubt that these enabling data technologies and tools will shape how we discover and develop new medicines in the future. This is not to say these new technologies will overtake or fully replace the established practices. We will have a clearer picture once we start to see more clinical stage assets that are significantly enabled or expedited by these technologies.   George Wu Co-Founder & CEO, Amberstone Biosciences George Wu is a life sciences technology innovator with great passion in developing innovative cross-field technologies to address unmet market needs. He has published over 40 manuscripts and abstracts in cancer biology, immunology, high-throughput drug discovery, single cell technologies, medicinal chemistry, and molecular diagnostics. With numerous patents relevant to anti-tumor molecules or single cell technologies, Wu is a recognized inventor committed to making a difference for the healthcare of patients. Before founding Amberstone, he was President/COO of GeneTex International, where he was closely involved in antibody and research product development, business scaling, and cross-border merger and acquisition. He received a BS in biology from the University of Science & Technology of China, and a PhD in molecular medicine from the University of Texas Health Science Center, San Antonio. As a Susan Komen Research Fellow at the University of California, Irvine, his primary focus was small molecule anti-tumor drug discovery and translational research.

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2022/08/11

Delivering on the Promise of New Modalities: An Interview with Andrea van Elsas, CSO, Abata Therapeutics, Venture Partner, Third Rock Ventures

As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs. In our latest interview, we’re joined by Andrea van Elsas, Venture Partner at Third Rock Ventures and CSO of Abata Therapeutics, a company focused on translating the biology of regulatory T cells (Tregs) into transformational medicines for patients living with severe autoimmune and inflammatory diseases. The company launched last year with $95 million in Series A Financing to engineer T cells to tackle autoimmune diseases like multiple sclerosis (MS). Most recently, Abata announced the formation of an advisory board comprised of leading industry experts in Treg Biology, Cell Therapy and Corporate Development. Hi Andrea, thanks for taking the time to join us today. Abata is developing targeted, autologous Treg cell therapies for serious autoimmune diseases. Could you please introduce your new modality approach to our audience? Andrea: Regulatory T cells (Tregs) have been well characterized during the past 25 years, demonstrating a wide palette of functions evolved to suppress or limit inflammation and support tissue repair. One of Abata’s founders, Diane Mathis, has led the field publishing a wealth of high impact studies unraveling a critical role for Tregs in limiting overactive immune responses and promoting repair in various organs and tissues. Tregs use several mechanisms to inhibit inflammation by cell-cell interaction as well as by secretion of soluble immunosuppressive factors into the inflamed milieu. These highly potent Treg functions dominate the activity of, for instance, effector T cells such as those found in the aforementioned meningeal lymphoid aggregates, and they can be triggered once the T cell receptor detects myelin-associated antigens produced locally upon tissue destruction. Importantly, by studying lymphocyte trafficking into the brain another Abata founder and CMO Richard Ransohoff showed that T cells require TCR activation by cognate antigen presented on meningeal macrophages to stay in the brain. Treg cell therapy has been clinically tested by a handful of teams during the past few years albeit not in progressive MS patients. Although Tregs were demonstrated to be safe, efficacy has not been optimal. We believe this is due to the fact that Tregs with the proper T cell receptors to direct them to the inflamed tissue are quite rare. By engineering a disease specific T cell receptor into Tregs we dramatically change the number of Tregs capable of trafficking into affected organs and treat ongoing disease using their polypharmacy capacity. It is a numbers game. Moreover, Treg cells are thought to stay around for a long time and differentiate into tissue-resident Tregs, potentially delivering highly durable clinical benefit even following a single dose of Tregs since durability matters in autoimmune disease. Also, in preclinical models Tregs are known to secrete factors that stimulate myelin repair adding to their potential durable benefit. In addition to progressive MS, the Abata team is currently working on specific TCR engineered Tregs for two other diseases, type 1 diabetes and inclusion body myositis. How your Treg approaches might make a difference to MS patients? Andrea: With our first product candidate ABA-101, Abata is aiming to treat patients with progressive MS. ABA-101 is an autologous Treg product that we engineer to express a specific T cell receptor to guide Tregs to the disease site, a discovery project run in close collaboration with Abata founder Roland Martin. Several approved drugs are currently available to treat patients with relapsing remitting MS with considerable success. However, after the flaring phase of the disease passes there are no effective options to treat progressive MS. At least in part this can be explained by the finding that 1) relapsing remitting disease is driven by immune cells that enter the meningeal compartment from the periphery (blood), 2) drugs effectively used to treat RRMS target leukocytes in the periphery, 3) in contrast, progressive MS is driven by lymphoid aggregates that have formed in the meninges secreting factors that activate myeloid and other cells destroying the myelin sheet locally, and 4) the currently approved drugs for MS do not appear to affect inflammatory activity originating from these meningeal lymphoid infiltrates. Learning from oncology, with TCR-engineered Tregs Abata is taking a first step to use the incredible potential of cell therapy in autoimmune diseases with highly unmet medical need. What are critical challenges in realizing the full potential of your new modality? What are Abata’s solutions? Andrea: First, TCRs represent a key element of this therapeutic approach, however self-antigen specific TCRs are very rare and the rules and tools for HLA class II-restricted TCRs are being developed. Second, as a therapeutic modality, autologous cell therapy requires robust investment in well-controlled manufacturing processes, facilities and teams. Third, endpoints demonstrating clinical activity of any product in progressive MS patients have been highly variable from patient to patient. Building from the TCR expertise of Abata founder Michael Birnbaum, Abata has recruited an exceptional team of scientist to set up and run an effective TCR discovery platform that includes optimizing the data science and tools for Treg functional studies and engineering. To maximize learning from the first few ABA-101 patient cohorts, Abata will exploit imaging technology that was developed by a Danny Reich, a key Abata advisor at the NIH, to allow quantitative determination of MS lesions before and after treatment. In addition to a variety of clinical biomarkers to determine Treg cell numbers and their activity in the meningeal compartment, we aim to show proof-of-principle for Abata’s TCR-engineered Treg platform. Following ABA-101, Abata aims to have three Treg products in clinical development by 2026. How would Abata harness the potential of novel data technologies, AI, or machine learning? Andrea: Abata recognized the potential high impact of AI and machine learning by working with existing experts at Third Rock Ventures as the company was being incubated. After its launch in 2021, Abata recruited a very strong data science team that now brings world class machine learning expertise to a variety of aspects that are critical to discover, manufacture and develop our Treg therapy. I believe we are only scratching the surface of possibilities for AI/machine learning in drug development and Abata is exploring novel applications as we speak. Thanks Andrea for your insights! Any closing thoughts? Andrea: In relation to Abata’s autologous engineered cell therapy product candidates, we aim to explore cutting edge science and technical solutions that might enable the production and application of Treg therapy at scale, to a much larger patient population than what the industry has dealt with thus far. A simple problem statement could be, how do we make Treg therapy available, not for 100 or 1000 patients, but for 100,000 patients per year.     Andrea van Elsas PhD Abata CSO and Venture Partner at Third Rock Ventures Andrea van Elsas is a venture partner with Third Rock Ventures (since 2020). He most recently served as Chief Scientific Officer at Aduro Biotech following the acquisition of BioNovion, a company he co-founded 2011. From 1999 to 2011, he held various positions at Organon (acquired by Schering-Plough and later by Merck) in Oss, The Netherlands, and Cambridge, Massachusetts. As Director of Tumor Immunology, he oversaw the immuno-oncology portfolio and led the anti-PD1 program that later became known as pembrolizumab. As a postdoctoral researcher, Andrea worked in the lab of Nobel Laureate Jim Allison at the University of California, Berkeley and is a co-inventor on the original anti-CTLA-4 patents that formed the basis for the development of ipilimumab, the first checkpoint inhibitor approved in 2011 by the FDA for the treatment of melanoma. He currently serves as CSO at Abata Therapeutics, on the Scientific Advisory Board of Lava Therapeutics (chair) and on the Supervisory Board of Immunicum and InteRNA Technologies.

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2022/08/11

Delivering on the Promise of New Modalities: An interview with Elvire Gouze, CEO & Founder, Innoskel SAS, France

As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs. The next installment of our interview series features Elvire Gouze, CEO & Founder of Innoskel SAS, France, a bioscience platform company developing transformative gene therapies for the unmet needs of individuals with rare bone disorders. When Innoskel launched at the end of 2020, they achieved Series A Financing to the tune of €20 million to advance the company’s lead program clinical stage operations. Innoskel is developing treatment options for a group of rare skeletal disorders collectively known as type 2 collagenopathies that affect the structure of the body’s connective tissues (collagen). Earlier this year, the company announced the enrollment of the first patient in a study, which will evaluate the course of type II collagen disorders in children with short stature. Thank you for taking the time to join us today, Elvire! We were excited to see early progress announced for your clinical trials earlier this year. For rare bone disorders, what are challenges in current therapeutic interventions, or current new modality solutions? Elvire: Innoskel is developing innovative treatments for rare bone disorders. These diseases affect the mechanisms of bone growth, mainly endochondral bone growth, and the challenge is to effectively target the growth plates of the bones of affected children while limiting off target distribution. There is no current modality for the diseases requiring gene therapy that have been shown to be effective at restoring bone growth. Indeed, common modalities, such as AAV or lipid nano particles, are known to be ineffective in targeting growth plates. Our approach is unique and a combination of the gene therapy modality, route of administration and proprietary promoter sequences allows us to have safety advantages combined with a directed biodistribution to the target tissues. How is your gene therapy approach helping to address this challenge? Is your technology differentiated from existing approaches? Elvire: Innoskel develops a lentiviral vector because of the ability of lentivirus to transduce non-dividing cells brings a significant advantage allowing genetic modification of the targeted proliferating cells and transmission to the daughter cells after cellular division. We have to pave the way with regulatory agencies and payers to address these diseases with a lentiviral vector administered systemically. The durability of the effect on bone growth is expected to be permanent – nevertheless, it is anticipated that due to bone growth and chondrocyte turnover, the duration of the LVV activity may be limited to 2-3 years requiring repeat administration. Innoskel is considering an immunomodulation regimen that should allow tempering down the immune reaction to the lentiviral vector and would allow for later redosing. In your opinion, what’s the biggest barrier to realizing the full potential of your LVV based gene therapies? Elvire: Manufacturing is a critical aspect of therapeutic intervention, and one must anticipate the technical challenges to accelerate treatment access for the patients. Indeed, current lentiviral vector production standards need to be optimized to reach a yield and product quality compatible with in vivo systemic administration. To solve these challenges and bring the therapies to global patients, how important is global collaboration to your company? Elvire: Global collaboration is critical for Innoskel. Indeed, when developing an innovative treatment for rare pediatric disorders, collaboration between companies, big pharmas and patient organizations is the only way to develop treatments and achieve patient access successfully and rapidly. Global collaboration is especially important in the rare disease area, where the best experts of these diseases are scarce and where the deep understanding of these diseases and their impacts on the life of patients is limited. It is essential to bring experts and patient representatives together to accelerate the development of therapies that are truly life-transforming and meaningful to patients. Worldwide databases and international collaboration are also critical to identify the few patients that could benefit from the treatment as quickly as possible, as we know that the therapeutic window before irreversible damages are done is tight in most cases. Looking for the best experts, wherever they are, allows us to be agile, creative, relevant and efficient. For Innoskel, the global collaboration approach is the best and only way to truly commit to patients to do the best we can to answer their high unmet needs. Thanks Elvire, really enjoy the discussion. If we were to gather here again in 10 or 15 years’ time, what do you think we’re going to be talking about in terms of what we have already achieved in the industry? What do you think are going to be some of the solutions going forward? Elvire: The real challenge for the next 10-15 years is to keep alive the interest of the pharmaceutical sector for rare diseases. Altogether rare diseases affect more than 400 million people worldwide. However, 95% of rare diseases have no approved treatment. The disinterest from the rare disease sector would be catastrophic and as a company, we need to be innovative to build a significant market case by regrouping diseases when possible. There are some solutions going forward such as the implementation of basket trials, allowing for the investigation of multiple rare diseases simultaneously with a single treatment intervention. Adaptive trial design is another solution that can be envisioned to accelerate the development of drug candidates for rare disease with high unmet needs.   Elvire Gouze, PhD CEO & Founder, Innoskel SAS, France Elvire Gouze is CEO and Founder of Innoskel. She is a distinguished researcher whose career represents a rare combination of scientific excellence, drug developmentand support for the patient community. Dr. Gouze has a proven track record of progressing the development of an innovative therapeutic pipeline, as seen with her first venture TherAchon, a biotech company focusing on achondroplasia, a rare bone disease, which was acquired at Phase 1 stage for $810M by Pfizer in May 2019. She holds a PhD in molecular pharmacology. She performed her post-doctoral training at Harvard Medical School, where she later became an Instructor in Orthopedic surgery in the Center for Molecular Orthopedics. Elvire Gouze was later appointed Assistant Professor at the University of Florida and in 2009 became Team Leader at Inserm Nice, France. Dr Gouze won twice the prestigious EY Entrepreneur of the year in the Startup category, PACA area, France.

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2022/08/09

Delivering on the Promise of New Therapies for Rare Diseases: An Interview with Ralph Laufer, CSO of Lysogene

Rare diseases represent a significant unmet medical need, impacting the lives of millions of patients and their caregivers worldwide. At WuXi AppTec, we believe that our ongoing collaborative efforts to raise disease awareness and foster innovative thinking will lead to better and faster breakthrough treatments to address the healthcare challenges of rare diseases. As we continue on this exciting journey to bring transformational medicines to patients, we are thrilled to share with you a new interview series from worldwide leading experts, “Delivering on the Promise of New Therapies for Rare Diseases.” Thank you for taking the time to join us, Ralph! Before we start, could you please introduce yourself for our audience? Ralph: My name is Ralph Laufer. I’m the Chief Scientific Officer of Lysogene, which is a gene therapy company located in Paris, France, and we are developing gene therapies for neurological diseases. At Lysogene, we have two clinical stage programs for the treatment of rare neurodegenerative lysosomal storage diseases, namely MPS IIIA, also known as Sanfilippo disease and GM1 gangliosidosis, as well as several discovery and preclinical stage programs that are focusing on Fragile X syndrome, Gaucher disease and related diseases, as well as neurodegenerative diseases. What inspired your work in the Fragile X field and what issues are you trying to address? Ralph: Lysogene’s mission is to develop novel gene therapy treatments for neurological diseases, and in particular rare genetic diseases, such as Fragile X. In 2018, we initiated a collaboration with the lab of Dr. Herve Moine from the IGBMC in Strasbourg, France, based on his discovery of a novel downstream target of FMR1 in neurons – the messenger RNA of an enzyme called diacylglycerol kinase kappa. We also call it DGKk in short. And the goal of this collaboration was to evaluate the therapeutic effect of DGKk delivered into the brain using an AAV vector in a mouse model of Fragile X. What approaches are you taking to gene therapies? Ralph: So Lysogene’s approach is gene therapy; and the most widely used gene therapy approach, also known as gene transfer or gene addition, involves delivery of a functional gene to substitute a missing or dysfunctional endogenous gene. Predominantly, this approach relies on the use of an innocuous and replication-deficient viral vector to transduce human cells, such as the adeno-associated virus or AAV vector. However, in the case of Fragile X syndrome, a gene transfer approach using the FMR1 gene presents several important challenges. First of all, FMR1 expression dosage is critical for normal cell condition and neuronal function, and duplications of the FMR1 gene are identified causes of intellectual deficiency. Therefore it would be very difficult to administer a gene therapy treatment which would require such a tight regulation of gene dosage. Secondly, the blood brain barrier, which is constituted by a barrier of cells that surround blood vessels in the central nervous system, impedes crossing of AAV vectors from the bloodstream into the brain parenchyma which is the site where pathology occurs. And therefore, Lysogene’s approach is to target a downstream effector of FMR1, the DGKk gene that I mentioned earlier, as well as to deliver the AAV vector carrying the therapeutic transgene directly into the CNS, bypassing the blood brain barrier. What is the greatest and differentiated value of your modality or technical approach to the treatment of Fragile X syndrome? Ralph: The current treatment for Fragile X remains largely insufficient and the care is primarily symptomatic, focusing on disease management without addressing the primary underlying mechanisms of disease. Importantly, current treatments do not constitute a solution for intellectual disability, which is one of the main features of Fragile X. We believe that focusing on DGKk, which is an immediate downstream target of FMR1 and neurons, offers the opportunity to correct one of the major disease mechanisms, and therefore has the potential of being disease modifying. Could you share with us your progress on this program so far, and what is the next milestone? Ralph: The approach we have taken is based on the identification by Dr. Herve Moine, our collaborator from the IGBMC, of DGKk, as the most proximal messenger RNA target of FMRP neurons. The absence of FMRP leads to the absence of DGKk, and the latter mimics the effect of FMR1-knockdown, both in vitro and in vivo. So to tackle this problem, we constructed an AAV that carries an FMRP-independent variant of DGKk, and we administered this vector directly into the brain of FMR1 knockout mice, which is a well-known animal model of Fragile X syndrome. And when we did this, it led to the correction of all behavioral abnormalities observed in the knockout mice relative to healthy wild-type mice. Also, treatment with this AAV was not associated with any overt toxicity in the mice. These findings were recently published in EMBO Molecular Medicine. We believe on the basis of these findings that gene therapy with DGKk holds considerable promise as a treatment option for Fragile X, and we are currently performing additional non-clinical studies to advance this candidate therapy into the clinic. In your opinion, are there any innovative collaborations or partnership models that the Fragile X community can pursue in order to advance the field faster? Ralph: I would say our collaboration with the lab of Dr. Moine at the IGBMC, as well as with Conectus, which is the technology transfer organization of the Alsace region here in France, were crucially important for the success of this program. The program relies on the combined know-how and expertise of one of the leading academic labs with expertise in Fragile X, molecular biology, and a gene therapy company such as Lysogene, which has expertise in AAV vector design, as well as nonclinical and clinical development of gene therapies, and regulatory affairs in the field. This type of academy-industry partnership, with very close collaboration between the scientists, joint project teams, regular meetings, and joint design of experiments, is in my opinion, a very efficient way to advance basic research into the clinic. Finally, what does patient-centric drug development mean for the Fragile X field? Ralph: For Fragile X, patient-centric drug development really means focusing on clinical outcomes that matter to patients. In drug development, there is an increasing focus on assessing patient and caregiver experiences and preferences. This is important for designing clinical trials that will have clinically meaningful outcome measures, but it is also important during nonclinical development, where we try to identify suitable animal models with phenotypes that can either reproduce or be related to a clinical relevant symptom or biomarker. Thank you very much for your participation and sharing your valuable insights with us. Ralph: Thank you.     Ralph Laufer CSO, LYSOGENE Dr. Ralph Laufer is the Chief Scientific Officer at Lysogene, a gene therapy company based in Paris, focusing on the development of innovative treatments for neurological diseases. Before joining Lysogene in 2018, Dr. Laufer was Senior Vice President and Head of Discovery and Product Development at Teva Pharmaceutical Industries. Prior to that, he held the positions of Scientific Director of IRBM Science Park, a drug discovery partnering organization in Rome, Italy, and Head of Pharmacology at IRBM-Merck Research Laboratories Rome. He is the recipient of the American Chemical Society 2013 Heroes of Chemistry Award for his role in the discovery and development of Isentress (raltegravir), the first integrase inhibitor approved for use in HIV infected patients. Dr. Laufer’s scientific achievements include the discovery of the tachykinin NK-3 receptor and the anti-obesity activity of ciliary neurotrophic factor. He is the author of over 90 peer-reviewed articles and inventor of more than 20 patents. Dr. Laufer obtained his PhD in Biochemistry (summa cum laude) and M.Sc. in Chemistry from the Hebrew University of Jerusalem. He conducted postdoctoral training at the Institut Pasteur in Paris.

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