Gene Replacement Therapy in Patients With Cardiac Disease: Challenges in Trial Design and Management of Adverse...

Gene replacement therapy has emerged as a promising strategy to address the underlying molecular defects in inherited and acquired cardiomyopathies, shifting treatment from symptom palliation to potentially disease-modifying interventions. Most clinical programs use adeno-associated viral vectors to deliver functional DNAs, demonstrating safety, durable myocardial transduction, and early improvements in biomarkers or imaging end points. However, the rarity and heterogeneity of target populations constrain trial size and duration, making traditional morbidity and mortality outcomes infeasible. Central to overcoming these challenges has been the concurrent establishment of rigourous natural history cohorts. They serve as external controls, allowing for the capture of exact disease trajectories to define the optimal effective therapeutic windows. Natural history studies are critical to identifying clinically meaningful surrogate end points, ranging from circulating biomarkers and quantitative imaging measures to composite functional ranks that integrate exercise capacity with patient-reported symptoms. Collaborating with regulatory authorities to identify composite outcomes that combine surrogate outcomes predictive of morbidity and mortality with innovative patient-reported outcomes, the obstacles of statistical power and hard outcomes can be overcome. Last, a comprehensive understanding of the immune response to viral capsids, together with optimized and validated immunosuppressive regimens, is much needed to deliver durable, disease-modifying therapies to patients with genetic cardiac diseases. Continued collaboration among investigators, regulators, and patient communities, including rigourous natural history study design, surrogate qualification, and innovative trial frameworks, will be essential to realize the full potential of gene replacement therapies in cardiology.