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 long-term 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.