ORIGINAL RESEARCH
Transpl. Int.
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
- KC
Krish C Dewan 1
- JC
Jeng-Wei Chen 1,2
- AA
Alejandro A Lobo 1
- RT
Ryan T Gross 1
- CW
Chunbo Wang 1
- KG
Karla G Rivera 1
- KD
Keely Dieplin Tran 1
- SN
Smith Ngeve 1
- VG
Violet G Johnston 1
- DW
David Wendell 3
- CK
Carolyn K Glass 4
- AE
Amy Evans 5
- SH
Sam Ho 6
- PL
Paul Lezberg 7
- WC
Widler Casy 8
- MB
Marla Bazile 8
- KP
Kruti Patel 8
- AS
Adam S Cockrell 8
- CA
Carmelo A Milano 1
- DE
Dawn E Bowles 1
1. Department of Surgery, Duke University Medical Center, Duke University, Durham, United States
2. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan, 100
3. Duke Cardiovascular Magnetic Resonance Center, Duke University Medical Center, Duke University, Durham, United States
4. Department of Pathology, Duke University Medical Center, Duke University, Durham, United States
5. Perfusion Services, Duke University Medical Center, Duke University, Durham, United States
6. Gift of Hope Organ and Tissue Donor Network, Itasca, IL, United States
7. TransMedics, Inc., Andover, MA, United States
8. Solid Biosciences Inc., Charlestown, United States, Massachusetts, 02129
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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 hours 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.
Summary
Keywords
Adeno-associated virus vector, gene therapy, heart transplantation, ex vivo heart preservation, transgene durability
Received
22 October 2024
Accepted
20 May 2025
Copyright
© 2025 Dewan, Chen, Lobo, Gross, Wang, Rivera, Tran, Ngeve, Johnston, Wendell, Glass, Evans, Ho, Lezberg, Casy, Bazile, Patel, Cockrell, Milano and Bowles. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Krish C Dewan, krish.dewan@duke.edu
Disclaimer
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