Creating superior lungs for transplantation with next-generation gene therapy during ex vivo lung perfusion

Engineering donor organs to better tolerate the harmful non-immunological and immunological responses inherently related to solid organ transplantation would improve transplant outcomes. Our enhanced knowledge of ischemia-reperfusion injury, alloimmune responses and pathological fibroproliferation after organ transplantation, and the advanced toolkit available for gene therapies, have brought this goal closer to clinical reality. Ex vivo organ perfusion has evolved rapidly especially in the field of lung transplantation, where clinicians routinely use ex vivo lung perfusion (EVLP) to confirm the quality of marginal donor lungs before transplantation, enabling safe transplantation of organs originally considered unusable. EVLP would also be an attractive platform to deliver gene therapies, as treatments could be administered to an isolated organ before transplantation, thereby providing a window for sophisticated organ engineering while minimizing off-target effects to the recipient. Here, we review the status of lung transplant first-generation gene therapies that focus on inducing transgene expression in the target cells. We also highlight recent advances in next-generation gene therapies, that enable gene editing and epigenetic engineering, that could be used to permanently change the donor organ genome and to induce widespread transcriptional gene expression modulation in the donor lung. In a future vision, dedicated organ repair and engineering centers will use gene editing and epigenetic engineering, to not only increase the donor organ pool, but to create superior organs that will function better and longer in the recipient.