Genetic engineering of kidney allografts by ex vivo perfusion delivery of adeno-associated viral vectors

Abstract
Despite advances in many domains, the field of solid organ transplantation remains limited by
two distinct but connected problems: (1) a critical shortage of donor organs and (2) suboptimal
graft longevity due to chronic alloimmune-mediated injury. For patients with end-stage renal
disease, these limitations are readily apparent, with over 90,000 individuals in the United States
awaiting kidney transplantation. This severe shortfall of donor kidneys is compounded by the
suboptimal longevity of transplanted allografts, with a median kidney graft survival of only 8-12
years despite advances in immunosuppression. These significant limitations indicate a clear
unmet need to develop novel approaches to improve the function of donor kidneys and enhance
graft longevity. The treatment of donor organs with gene therapies has long been recognized as
a promising strategy to enhance graft function and diminish graft immunogenicity, but until
recently there have not been feasible approaches for gene delivery in an organ-specific manner.
Over the last decade, the clinical development of ex vivo organ perfusion systems has created
an ideal platform for selectively delivering gene therapies directly to donor allografts. Advancing
this approach toward clinical use requires testing in a non-human primate transplant model
using clinically relevant immunosuppression regimens. For this proposal, we have assembled a
team of investigators with expertise in ex vivo organ perfusion, the use of adeno-associated viral
(AAV) vectors for gene therapy, immune management, and kidney transplantation. We have 3
specific aims: 1) Optimize ex vivo machine perfusion approaches for delivery of gene therapies
to kidney grafts in an auto-transplant model, 2) Determine the impact of the alloimmune
response on transgene expression in kidney allografts, and 3) Evolve novel AAV vectors with
tropism for human kidney grafts. Successful completion of this project will demonstrate the use
of genetic engineering approaches to achieve durable transgene expression in kidney grafts.
This approach has the potential to establish a new paradigm of genetically augmented solid
organ allografts and transform approaches in solid organ transplantation.

Grant Number: 5U01AI170064-05
NIH Institute/Center: NIH
Principal Investigator: Andrew Barbas