From Discovery To Delivery: Accelerating The Path Forward For Gene Therapies
A conversation with Manny Otero, Ph.D., and Sandi See Tai, MD, Lexeo Therapeutics
Gene therapies offer immense promise due to their potential to treat a wide range of genetic diseases by targeting the underlying cause of the disease at the genetic level. Unlike traditional treatments that primarily manage symptoms, gene therapy aims to counteract the effects of pathogenic mutations and restore healthy function, potentially providing a long-lasting therapeutic solution. Developing this novel science, from discovery through clinical development to then scaling these treatments for manufacturing and delivery, has required innovation and adaptability to today’s environment.
Lexeo Therapeutics’ Manny Otero, Ph.D., and Sandi See Tai, MD, explore key strategies to advance gene therapies, including clinical trial design, academic partnerships, regulatory approaches, and manufacturing frameworks, and highlight some of the steps Lexeo has taken to navigate gene therapy development in cardiology.
Industrywide in drug discovery/design for gene therapies, what needs to happen in order to usher in the next era of gene therapies, and how do we get there?
Tai: The first thing we need is continued flexibility and regulatory innovation. For rare genetic diseases, particularly those with devastating consequences and few treatment options, time is of the essence. Of course there must be a rigorous standard of review, but large and lengthy trials – which are historically common in cardiovascular research – can be detrimental to patients in need today. This challenge is even more pronounced in pediatric populations, where traditional drug development usually begins in adults and may take years to extend to younger patients. As Ron Bartek, president and cofounder of the Friedreich’s Ataxia Research Collaboration (FARA), says, we need to stop protecting children from clinical trials and start protecting children with clinical trials – especially if those children are suffering the effects of debilitating conditions like FA.
We’ve been fortunate to partner with the FDA to date on innovative trial design, such as the use of surrogate endpoints and natural history comparator arms, that offer the flexibility needed to efficiently advance the next generation of gene therapies. There are thousands of rare diseases, and millions of people without effective treatment options today, so we need the ability to design trials that are fit-for-purpose.
Otero: In parallel with flexible and creative clinical trial designs supported by an enabling regulatory framework, we need to solve the gene therapy manufacturing challenges of high cost of goods, lack of scalability, and limited manufacturing robustness and consistency. Our industry is making remarkable scientific advances, but few gene therapy programs have demonstrated true commercial scalability and success. The way Lexeo is combatting this challenge is through building a manufacturing platform for viral vectors that aims to set a high standard in AAV drug substance and drug product manufacturing. This means achieving high volumetric yield alongside a quality attribute profile that ensures safety and efficacy — all while maintaining cost of goods that support commercial viability from the outset of clinical development.
Tai: The last thing I will add is on gene therapy safety. Gene therapy development must always begin and end with the patient in mind, and benefits and risks must be weighed in the context of the disease. It is our responsibility to find the dose that can deliver durable efficacy while minimizing risk. For example, in our clinical programs, we’ve been able to administer doses that are relatively lower for the field due to the capsid we are using, AAVrh10. To date, we have not observed any clinically significant complement activation in our clinical studies. Ultimately, every gene therapy manufacturer must continue to evaluate long-term safety in humans so we can build a robust understanding for the field.
What is Lexeo’s strategy in partnering with and working with academic institutions? What’s your advice for other therapy companies looking to partner more with academia?
Tai: At Lexeo, we’ve always seen academic partnerships as key to driving innovation in genetic medicine. Some of the most exciting and impactful ideas are born in academic labs, and we’ve licensed multiple programs that started in these settings. We also know that developing a therapy takes more than discovery, and that’s where a company can sometimes operate more efficiently. It’s about knowing when to transition from early promise to focused execution.
Otero: We also stay really connected to our academic roots throughout development. Through sponsored research agreements and our scientific advisory board, we continue to collaborate with industry leaders. A great example is our ongoing partnership with Weill Cornell Medicine. As Lexeo is running a Phase 1/2 trial in Friedreich ataxia (FA) cardiomyopathy, Ron Crystal, MD, is also running a Phase 1 investigator-initiated trial in parallel at Weill Cornell. We have partnered closely with Dr. Crystal to ensure that his academic insights and clinical trial data can be pooled with Lexeo data as we meet with regulators and work to understand the totality of evidence for gene therapy in this disease. This collaboration has allowed us to accelerate research and exemplifies the power of close alignment between academic science and industry development.
How is Lexeo tackling preclinical challenges associated with gene therapies?
Otero: Preclinical development can be time-consuming and resource-intensive, both of which are challenging in this biotech environment, so we’ve tried to build efficiencies around a platform approach. In our lead gene therapy programs, we are using a single well-characterized vector — AAVrh10 — that demonstrates a strong affinity for cardiac tissue, which is central to our focus on cardiac genetic medicine. We’ve also built a deep understanding of its safety, optimal dosing, manufacturing, and performance over time. That consistency across the platform helps us to move faster and with more confidence, both in the clinic and in preclinical work, and provides a strong anchor for data-driven regulatory flexibility.
We also know how to manufacture AAVrh10 at scale, which we have demonstrated across multiple clinical development programs up to 200-L GMP bioreactor scale. That know-how translates across programs and allows us to leverage CMC efficiencies, so we can move seamlessly from a new gene of interest to representative materials for enabling toxicology studies and to GMP drug product delivered to clinical sites in a very short time. If your drug works, you know you have line of sight to a commercial manufacturing process and supply chain before dosing a single patient.
Tai: Pursuing the most promising preclinical science is essential for innovation, but finding the right partners and funding can be a challenge for many companies. Lexeo has tried to find creative solutions and a recent example is the company’s partnership with Perceptive Advisors and venBio Partners. The collaboration will focus on advancing cardiac RNA therapeutics using novel non-viral delivery, within a new entity but founded with Lexeo’s IP and know-how. It’s a unique structure and one that will allow us to continue to innovate and potentially even accelerate progress toward key development milestones, even with the challenges of this market.
What is Lexeo’s overall approach to the clinical development of gene therapies for cardiovascular diseases?
Tai: We’ve built a pipeline around genetically defined cardiac conditions because we believe genetic medicines can have significant clinical impact. Our research in gene therapy requires specific development priorities. Because diagnosis of rarer conditions is often delayed, we have to support and prioritize early patient identification, expanded genetic testing, and close collaboration with centers of excellence to help bring patients to experienced sites for research and care.
We also work very closely with patient advocacy groups to shape trials around what truly matters to those living with these conditions. Our trial designs emphasize early intensive monitoring to ensure safety while also measuring biomarkers that can signal efficacy more rapidly, which is critical for research in conditions with high unmet need. These biomarkers may also serve as surrogate endpoints in regulatory discussions, enabling more efficient development.
Shipping/logistics of gene therapies is complex. How is Lexeo Therapeutics approaching this for clinical trial supply, and what are Lexeo’s plans for scaling up after regulatory approval?
Otero: We’re building our manufacturing platform with the end in mind, embedding commercial efficiency, scalability, robustness, and consistency into the process, analytics, quality control, and supply chain from day one, well before the first patient is ever dosed. We accomplish this with internal CMC subject matter experts and leading experimental capabilities, and we also build deep partnerships across a supply network of development, testing, manufacturing, and logistics companies. This framework allows us to de-risk scientific and technical challenges early and move quickly if initial studies are positive.
Tai: From a clinical perspective, we’re very aware that gene therapy is still relatively new territory for many cardiologists. There are, however, many centers of excellence that have some experience with therapies like Zolgensma, and we want to ensure we are involving the multidisciplinary care team from the beginning. This is true in our clinical trials today but it will remain critical in any commercial setting. Because this is such a novel modality, the perspectives of those with gene therapy experience are invaluable, not just for managing logistical complexity but also for ensuring patients get the best possible care throughout the treatment process.
Ultimately, this is what every person at Lexeo is working toward. We’re very motivated to think about regulatory approval and beyond — as we’re striving to bring promising genetic medicines to those living with devastating cardiac conditions as quickly as possible.
About The Experts:
José Manuel (Manny) Otero, Ph.D., joined Lexeo in 2024. He was previously chief technical officer at Auregen Biotherapeutics, leading R&D and manufacturing in the development of autologous 3D bioprinted cell-based restorative anatomy in Phase 1b/2 clinical development for patients suffering from microtia. Prior to joining Auregen in 2023, Otero was chief technology officer at Turnstone Biologics, where he was responsible for building and leading bioprocess development, manufacturing, supply chain, quality control, and CMC. He came to Turnstone from his position as vice president, bioprocess development and manufacturing of Seres Therapeutics. He was similarly an early member of CMC leadership and oversaw the expansion of the bioprocess development and manufacturing group. Otero received his Ph.D. in biological and chemical engineering from Chalmers University of Technology as a Merck Doctoral Fellow, an M.E. in biomedical engineering form the Massachusetts Institute of Technology, and a B.S. degree in chemical engineering from the Massachusetts Institute of Technology.
Sandi See Tai, MD, joined Lexeo in 2023. Prior to Lexeo, Tai was VP & development head for rare disease at Pfizer, where she was responsible for setting the rare disease internal portfolio strategy and delivering its clinic development portfolio of investigational products and in-line assets. She has served as the medicine team lead for clinical programs across multiple therapeutic areas, including rare cardiovascular, neurology, renal, and pulmonary disease areas, including leading the late-stage clinical development program of tafamidis for ATTR cardiomyopathy, which achieved global regulatory approvals. With almost 20 years of experience in the pharmaceutical industry, she has held roles of increased scope and responsibilities across global medical affairs in transplantation at Wyeth Pharmaceuticals before moving into clinical development at Pfizer. Prior to joining the industry, Sandi was assistant professor of pediatrics at Drexel University College of Medicine and attending physician in pediatric nephrology at St. Christopher’s Hospital for Children, Philadelphia. She received her MD from Tufts University School of Medicine, Boston.