Cross-species evolution of capsid libraries for gene delivery to the kidneys

Abstract

Effective gene delivery to the kidneys is complicated by the intricacies of kidney anatomy and physiology, and cross-species differences create further barriers in the translation of preclinical research. A study by Aravind Asokan and colleagues now demonstrates the potential of adeno-associated virus (AAV) library evolution for the development of human kidney gene therapies.

Delivery of AAV.k13 and AAV.k20 intravenously in mice not only led to higher mCherry expression compared with the parental AAV9 variant, but was also effective for the delivery of a programmed death ligand 1 (PD-L1) transgene, with evidence of robust PD-L1 expression in the kidneys after 4 weeks. In pig kidney grafts, retrograde ureteral delivery of mCherry packaged in the new AAV variants resulted in broad protein expression throughout the proximal tubules, with lower levels in the distal tubules, following transplantation into the same animal. Despite no differences in viral biodistribution, kidney expression levels of mCherry mRNA were significantly higher when the transgene was packaged in the new AAV variants compared with the parental AAV9 capsid.