Current Landscape of Heart Failure Gene Therapy.

Abstract

Gene therapy for patients with HF is now on the cusp of being successfully translated from the laboratory to the clinical arena. It is no longer a theoretical vision, but a realistic opportunity for the future treatment of patients with HFrEF. This transition is attributed to an increased understanding of the optimization of the various AAV serotypes, a better understanding of the efficacy of the various cardiac‐restricted promoters, and clarification of the most effective delivery systems. Although recent studies in humans did not prove efficacious, they were of great importance because they demonstrated the safety of gene therapy and defined the methods for gene delivery. Nonetheless, challenges remain. First, the development of AAVs that are nonimmunogenic will allow treatment of patients with preexisting AAV antibodies and will obviate, or at least lessen, the risk of the development of adaptive immunity. Second, the construction of AAVs that can package large genes will facilitate the generation of new therapies for individuals with mutations that are not currently approachable (eg, titin and lamin) or that require indirect approaches. Third, the identification of new HFrEF‐causing mutations in large‐scale genomic studies, such as the recently initiated All of Us study, will expand the number of patients who can benefit from gene therapy. And, finally, development of highly cardiac trophic vectors may allow therapy to be delivered intravenously rather than intracoronary with comparable or greater efficiency of transduction.