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
Journal
Transplant International
Journal Volume
38
ISSN
1432-2277
Date Issued
2025-06-02
Author(s)
Dewan, Krish C.
Lobo, Alejandro A.
Gross, Ryan T.
Wang, Chunbo
Rivera, Karla G.
Tran, Keely Dieplin
Ngeve, Smith
Johnston, Violet G.
Wendell, David
Glass, Carolyn K.
Evans, Amy
Ho, Sam
Lezberg, Paul
Casy, Widler
Bazile, Marla
Patel, Kruti
Cockrell, Adam S.
Milano, Carmelo A.
Bowles, Dawn
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.
Subjects
adeno-associated virus vector
ex vivo heart preservation
gene therapy
heart transplantation
transgene durability
SDGs
Publisher
Frontiers Media SA
Type
journal article