Potential Applications for Targeted Gene Therapy to Protect Against Anthracycline Cardiotoxicity JACC: CardioOncology Primer

Anthracyclines are associated with risk of significant dose-dependent cardiotoxicity. Conventional heart failure therapies have neither ameliorated declining cardiac function nor addressed the underlying cause. Gene therapy may confer longterm cardioprotection by rendering the heart resistant to anthracyclines after 1 treatment, although the optimal therapeutic target remains to be elucidated. Recombinant adeno-associated virus is now clinically approved for the treatment of lipoprotein lipase deficiency, spinal muscular atrophy, and hereditary transthyretin amyloidosis. High-throughput methods allow selection of recombinant adeno-associated virus capsids that facilitate efficient gene delivery to specific target cells. Vector safety is enhanced by incorporating cardiac-specific promoters into vector design and localizing delivery to reduce off-target risk. Any cardioprotective transgene may bear a degree of risk as they may play as yet unknown roles, which require careful assessment using clinically relevant models. The innovative technologies outlined here make gene therapy a promising proof of principle, with potential further application to nonanthracycline chemotherapeutics. (J Am Coll Cardiol CardioOnc 2021;3:650-662) (c) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).