rAAV9 combined with renal vein injection is optimal for kidney-targeted gene delivery: conclusion of a comparative study

Effective gene therapy strategies for the treatment of kidney disorders remain elusive. We report an optimized kidney-targeted gene delivery strategy using recombinant Adeno-Associated Viruses (rAAV) administered via retrograde renal vein injection in mice. Renal vein injection of rAAV consistently resulted in superior kidney transduction compared to tail vein injection using as little as half the tail vein dose. We compared rAAV 5, 6, 8 and 9, containing either GFP or luciferase reporter genes driven by the CMV promoter. We demonstrated that although rAAV6 and 8 injected via renal vein transduced the kidney, transgene expression was mainly restricted to the medulla. Transgene expression was systematically low after rAAV5 injection, attributed to T-cell immune response, which could be overcome by transient immunosuppression. However, rAAV9 was the only serotype that permitted high transduction efficiency of both the cortex and medulla. Moreover, both the glomeruli and tubules were targeted, with a higher efficiency within the glomeruli. To improve the specificity of kidney-targeted gene delivery with rAAV9, we used the Parathyroid hormone “kidney-specific” receptor promoter. We obtained a more efficient transgene expression within the kidney, and a significant reduction in other tissues. Our work represents the first comprehensive and clinically relevant study for kidney-gene delivery.