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

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

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-tropi...

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Main Authors: Krish C. Dewan, Jeng-Wei Chen, Alejandro A. Lobo, Ryan T. Gross, Chunbo Wang, Karla G. Rivera, Keely Dieplin Tran, Smith Ngeve, Violet G. Johnston, David Wendell, Carolyn K. Glass, Amy Evans, Sam Ho, Paul Lezberg, Widler Casy, Marla Bazile, Kruti Patel, Adam S. Cockrell, Carmelo A. Milano, Dawn Bowles
Format: Article
Language:English
Published: Frontiers Media S.A. 2025-06-01
Series:Transplant International
Subjects:
adeno-associated virus vector
gene therapy
heart transplantation
ex vivo heart preservation
transgene durability
Online Access:https://www.frontierspartnerships.org/articles/10.3389/ti.2025.13971/full
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Summary: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.
ISSN:1432-2277

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