Delivery Strategy For Next-Gen Cardiac Gene Therapies

By Narinder Bhalla, MD, chief medical officer, and José Manuel Otero, Ph.D., chief operating officer, Lexeo Therapeutics

Advances in cardiac genetic medicine are reshaping what is possible for patients with inherited and acquired heart disease. Yet as the field matures, the central challenge is no longer simply identifying the right genetic targets; it is delivering therapeutic payloads precisely, efficiently, and safely to one of the most structurally complex and metabolically demanding organs in the body: the heart. Progress now depends on integrating molecular design with delivery device innovation and novel routes of administration strategies that can unlock the full potential of cardiac gene therapy.

The Heart As A Delivery Environment

Cardiac tissue presents a unique set of biological constraints. Cardiomyocytes are densely packed, terminally differentiated cells with limited proliferative capacity. Low cardiomyocyte turnover underpins the promise of gene therapy to treat cardiac diseases, given the potential for lasting therapeutic expression following a single administration. Yet the high coronary blood flow rate (resulting in a fast transit time), constant torquing and contracting of the cardiomyocytes, and a robust and active extracellular matrix are all challenges that need to be overcome to allow for adequate viral vector penetration. Add to this the presence of an increased extracellular volume, signaling fibrosis in many disease states, and the issue of vector penetration compounds.

At the cellular level, vector tropism, capsid–receptor interactions, and intracellular trafficking determine whether a therapeutic gene reaches its intended destination. AAV serotypes with natural cardiotropism, such as AAVrh10, demonstrate improved transduction efficiency and an ability to achieve robust expression at lower doses than many traditional serotypes. While such vectors have unlocked therapeutic potential in certain cardiac indications to date, other conditions require expression at such a high level that systemic intravenous dosing creates new risks, namely off-target exposure and dose-related viral toxicities. As a result, the field is increasingly exploring targeted delivery routes that may maximize local exposure while minimizing systemic burden.

Targeted Delivery Opens New Therapeutic Horizons

Emerging targeted delivery strategies are changing what is possible. Intracoronary infusion is one such approach, with multiple research programs currently in the clinic. By delivering viral vectors through the coronary arteries with catheter-based procedures, it may be possible to enhance myocardial uptake while reducing systemic viral exposure. Techniques that temporarily modulate coronary flow or pressure can further improve dwell time and, potentially, tissue penetration. These methods require careful coordination with interventional cardiology teams, but they demonstrate how drug device innovation can enhance what cardiac gene delivery can achieve.

Localized cardiac pumps and catheter-based perfusion systems represent another promising frontier. These devices can deliver vectors directly to specific myocardial regions under controlled flow conditions, improving penetration and potentially reducing washout, as shown in a porcine model. While specific platforms vary, these new methods create opportunities to revisit targets previously considered untreatable given potential for enhanced vector residency and greater transduction efficiency.

To date, these innovative techniques have primarily been tested in animals or in limited human studies, focusing on those with end-stage heart failure (e.g., NYHA Class III) or severe cardiac distress. As research expands, their applicability is expected to grow into broader patient populations, accelerating through collaborations between genetic medicine developers and companies with expertise in cardiovascular health and technology. Recent partnerships in the field reflect a shared recognition that cardiovascular delivery devices will be essential to unlocking the next generation of cardiac genetic medicines.

Aligning Vector Engineering With Delivery Strategy

Optimizing cardiac gene therapy requires aligning vector engineering with delivery mechanics. Several principles are emerging:

• Capsid selection must match the delivery route. For example, the cardiotropic profile of AAVrh10 makes it well suited for both intracoronary and localized perfusion approaches, where its natural targeting efficiency can be leveraged at lower doses. Emerging engineered capsids could provide similar benefit, although further clinical data is needed to characterize safety and efficacy profiles in humans.
• Promoter choice shapes safety and specificity. While localized delivery may reduce off-target biodistribution, cardiac-specific promoters offer an additional mechanism to manage potential downstream effects that may emerge with new delivery platforms.
• Formulation matters. Vector concentration, potency, and quality will shape therapeutic distribution and local tissue responses, particularly as targeted delivery increases the intensity of cardiac exposure. Drug manufacturers may have an edge if they can demonstrate consistent product quality across small and large manufacturing lots, robust process reproducibility, and a favorable impurity profile alongside low empty-to-full capsid ratios.
• Transient modulation of cardiac physiology may enhance uptake. Adjusting coronary flow or pressure during delivery may improve vector dwell time and transduction.
• Study vectors and devices in parallel. Partnerships between gene therapy developers and cardiovascular device companies are accelerating this convergence. These collaborations bring together expertise in vector biology, interventional cardiology, and device engineering, all essential components to solve the delivery challenge.

These molecular and physiological considerations must be integrated early in development so device-enabled delivery becomes a core component of therapeutic and clinical trial design.

Manufacturing As A Strategic Enabler

Scalable, consistent, and robust manufacturing is increasingly central to the success of viral vector-based gene therapies, particularly as delivery becomes more targeted and efficient and as new indications become viable in larger patient populations. This shift demands development of manufacturing platforms that can produce high-quality viral vectors at a favorable total cost of goods, with consistency in quality across batches and flexibility across serotypes and formulations.

As an example, Lexeo’s insect cell culture (Sf9) baculovirus manufacturing platform is built with scalability in mind, supporting both systemic and localized delivery approaches. As genetic medicine research expands into broad indications such as cardiomyopathy and heart failure, it is critical that manufacturing platforms maintain vector quality at scale, enable a relatively simple global supply chain, ensure a highly favorable cost profile, and leverage the regulatory and industrial synergies resulting from a platform with significant human safety and efficacy experience across different target diseases. Gene therapy may only reach large cardiovascular populations if manufacturers leverage the approaches and technologies used in global vaccine and traditional biologics manufacturing, as opposed to what has been historically observed in rare disease: limited volumetric scaling, complex supply chains for starting materials, costly per dose manufacturing, and variable consistency of key quality attributes. Preparing for that future means investing in next-generation platforms capable of delivering consistent high-quality vectors at commercial scale during early clinical-stage development, so that manufacturing capacity is no longer a downstream consideration but rather part of the value creation proposition for patients.

Toward A New Era Of Cardiac Genetic Medicine

Cardiac gene therapy is entering a new phase, one defined by precision delivery and multidisciplinary innovation. As the field moves toward treating conditions such as inherited cardiomyopathies, arrhythmogenic disorders, and heart failure syndromes — some of which are more prevalent than others — success will depend on our ability to deliver genetic medicines exactly where they are needed, in the right amount, at the right time.

The integration of molecular engineering with advanced delivery technologies is transforming what is possible. By exploring device-enabled routes of administration, the field is laying the foundation for a future in which cardiac gene therapy could become a routine, durable, and life-changing option for patients. As we advance, the most transformative therapies will be those that treat delivery not as an afterthought but as a fundamental design principle that could even reshape the future of heart health.

About The Authors:

Narinder (Nani) Bhalla, MD, joined Lexeo as chief medical officer in 2026. Bhalla is a physician-executive with more than 20 years of experience as an interventional cardiologist and nearly a decade of leadership in the biopharmaceutical industry. Since transitioning to industry in 2015, he held senior leadership roles at AstraZeneca and Bristol Myers Squibb, where he most recently served as senior vice president and head of global medical affairs, immunology & cardiovascular. Bhalla is widely recognized for building and scaling high-impact medical and clinical development organizations as well as leading successful global product launches that deliver meaningful outcomes for patients. Bhalla completed his training at NYU Langone Medical Center. He received his MD from the University at Buffalo and his B.S. from Binghamton University.

José Manuel (Manny) Otero, Ph.D., is chief operating officer at Lexeo Therapeutics. He joined the company as chief technical officer in 2024. Otero 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 Seres Therapeutics, where he was similarly an early member of CMC leadership and oversaw the expansion of the bioprocess development and manufacturing group. Otero began his career at Merck, holding various leadership roles in the vaccine business unit. Otero received his Ph.D. in biological and chemical engineering from Chalmers University of Technology as a Merck Doctoral Fellow, his M.E. in biomedical engineering from the Massachusetts Institute of Technology, and his B.S. degree in chemical engineering from the Massachusetts Institute of Technology.