Delivery of a Muscle-Targeted Adeno-Associated Vector Via Ex Vivo Normothermic Perfusion Is Efficient, Durable, and Safe in a Preclinical Porcine Heart Transplant Model

Abstract

Normothermic ex-vivo organ perfusion (EVP) systems not only provide a physiological environment that preserves donor organ function outside the body but may also serve as platforms for ex-vivo organ modification via gene therapy. In this study, we demonstrated that a rationally designed muscle-tropic recombinant AAV, AAV-SLB101, delivered to the donor heart during brief normothermic EVP achieves durable cardiac transgene expression out to 90 and 120 days post-transplant in a porcine preclinical model. Moreover, transgene expression was detectable as early as 48 h post-transplant. Histological and MRI analyses of the donor myocardium showed no functional or structural impact on the allograft and no off-target gene expression in the recipient. This work will serve as a critical foundation to inform translational studies with therapeutic transgenes to improve allo-, xeno-, and auto-heart transplant outcomes.

Keywords: adeno-associated virus vector; ex vivo heart preservation; gene therapy; heart transplantation; transgene durability.