Genetically engineered organs for early reporting of transplant rejection

Abstract

Diagnosis of organ transplant rejection remains limited by the low sensitivity and specificity of blood tests and the invasive nature of biopsies. This study introduces an innovative approach for detecting rejection through the genetic modification of transplant organs. Using lentiviral vectors, we delivered immunoresponsive transgenes to vascularized composite allografts during ex vivo normothermic machine perfusion. This enabled in situ detection of rejection via secretion of the reporter protein Gaussia luciferase (GLuc) into the circulation. We demonstrated long-term stability of constitutive transgene expression beyond 500 days, the human equivalent of about 50 years. When GLuc expression was driven by a synthetic nuclear factor kappa B promoter, these inflammation-responsive organs enabled the non-invasive monitoring of rejection that preceded histological changes by 6 days. Our findings demonstrate the potential of combining gene therapy and machine perfusion to enhance the diagnostic capabilities of transplantable organs, offering a promising avenue for improving long-term graft survival and patient outcomes in transplant medicine.