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Review
. 2023 Oct 16:10:1264449.
doi: 10.3389/fcvm.2023.1264449. eCollection 2023.

Gene therapy during ex situ heart perfusion: a new frontier in cardiac regenerative medicine?

Mats T Vervoorn  1 , Jantijn J G J Amelink  1 , Elisa M Ballan  1   2   3 , Pieter A Doevendans  3   4 , Joost P G Sluijter  2   5 , Mudit Mishra  2 , Gerard J J Boink  6   7 , Dawn E Bowles  8 , Niels P van der Kaaij  1
Affiliations
Review

Gene therapy during ex situ heart perfusion: a new frontier in cardiac regenerative medicine?

Mats T Vervoorn et al. Front Cardiovasc Med. .

Abstract

Ex situ organ preservation by machine perfusion can improve preservation of organs for transplantation. Furthermore, machine perfusion opens up the possibilities for selective immunomodulation, creation of tolerance to ischemia-reperfusion injury and/or correction of a pathogenic genetic defect. The application of gene modifying therapies to treat heart diseases caused by pathogenic mutations during ex situ heart perfusion seems promising, especially given the limitations related to delivery of vectors that were encountered during clinical trials using in vivo cardiac gene therapy. By isolating the heart in a metabolically and immunologically favorable environment and preventing off-target effects and dilution, it is possible to directly control factors that enhance the success rate of cardiac gene therapy. A literature search of PubMed and Embase databases was performed to identify all relevant studies regarding gene therapy during ex situ heart perfusion, aiming to highlight important lessons learned and discuss future clinical prospects of this promising approach.

Keywords: ex situ heart perfusion; gene therapy; heart failure; heart transplantation (HTx); regenerative medicine.

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Conflict of interest statement

GB reports ownership interest in PacingCure BV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic overview of potential applications of gene therapy during ex situ heart perfusion (ESHP). (A) Gene therapy of a heart with a pathogenic mutation, followed by autotransplantation. The patient is connected to a cardiopulmonary bypass (CPB) circuit during ex situ treatment of the diseased heart. (B) Gene therapy during ex situ heart perfusion for biological modification, e.g. immunomodulation, followed by orthotopic heart transplantation. The figure was constructed using Biorender.com.
Figure 2
Figure 2
Gene therapy during ESHP has been investigated for immunomodulation and to decrease ischemia-reperfusion injury (IRI). Immunomodulation was conducted by transduction of cardiomyocytes with adenoviral vectors that carried genes encoding anti-inflammatory cytokines (IL-4, IL-10, TGF-beta, and CTLA4IG. IRI was attenuated by adenoviral mediated gene transfer of manganese superoxide dismutase, nitric oxide synthase and heat shock protein 70. ESHP: ex situ heart perfusion. IL: interleukine. PGD: primary graft dysfunction. DAMPS: damage-associated molecular pattern. The figure was constructed using Biorender.com.
See this image and copyright information in PMC

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