Preserve, Edit, Transplant: Reinventing Organs through Genetic Engineering

Abstract

Severe traumatic disfigurements significantly limit patients' quality of life, yet effective reconstructive options are limited. Vascularized Composite Allotransplantation (VCA), such as face or hand transplants, uniquely offers genuine restoration of form and function. However, VCA faces even greater challenges than solid organ transplantation, notably short preservation times due to muscle ischemia sensitivity (6 hours compared to 24 hours for kidneys) and high rejection rates from skin immunogenicity, affecting nearly 90% of recipients despite intensive immunosuppression. This thesis addresses these challenges through innovative integration of gene therapy and advanced preservation technologies, employing ex vivo machine perfusion. Specifically, the development of a novel genetic engineering platform for whole organs was established, demonstrating robust, and durable genetic modification, capable of facilitating early and precise detection of rejection through minimally-invasive approaches. To overcome preservation limitations, subzero non-freezing or ‘supercooling’ protocols were developed and optimized for VCAs, extending preservation time and reducing the rate of graft failure due to ischemia-reperfusion injury and rejection. In conclusion, this thesis lays the groundwork for combining ex vivo genetic engineering and advanced preservation as a transformative approach to the future of transplantation. Framed as Preserve, Edit, Transplant, this opens pathways for reinventing organs through the creation of ‘smart organs’, capable of autonomously modulating or responding to their environment. Collectively, these advancements expand transplant possibilities, offering potential improvements in clinical outcomes and enhanced quality of life for patients requiring complex reconstructive transplantation.