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

Abstract

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.

Recent development and gene therapy for glycogen storage disease type Ia

“…43,46,48 Different AAV serotypes have different tissue transduction efficiencies and more recent data suggest that rAAV2/9 may be the preferred choice for future renal gene delivery. 49–52 However, rAAV2/9-mediated transgene expression in the kidney is still significantly lower than that in the liver. Using a retrograde renal vein injection method, Rocca et al .…”

“…Using a retrograde renal vein injection method, Rocca et al . 52 showed that rAAV2/9-mediated kidney transduction could be markedly improved. Identification of viral serotypes that effectively transduce all affected tissue types remains to be further explored.…”

Hydrodynamic Renal Pelvis Injection for Non-viral Expression of Proteins in the Kidney

“…Future electron microscopy studies may elucidate this mechanism further. The retrograde nature of the injection has precedence in that the hydrodynamic tail vein injection method reverses the flow of the hepatic vein 20 and other successful methods of kidney transfection have injected via the renal vein 12–14,21 . Kidney damage is likely required for optimal transfection efficiencies so we hypothesize that transfection occurs via damage to the cell membrane caused by the fast, high-volume injection.…”

Inherited Kidney Disorders in the Age of Genomics

“…Also, its use has been reported to be safe and effective in various clinical trials [97][98][99][100][101]106,109]. With respect to gene delivery, different approaches can be used to target the kidney to achieve expression of the transgene in proximal and distal tubules, glomeruli, and the peritubular interstitium [106,111,112]. With respect to gene delivery, different approaches can be used to target the kidney to achieve expression of the transgene in proximal and distal tubules, glomeruli, and the peritubular interstitium [106,111,112].…”

“…There are various variants (>10) of AAV available; these are referred to as "serotypes," and each has different tissue-specific induction capacities [110]. For example, it was recently shown that injection of recombinant AAV serotype 9 in the murine renal vein is effective for renal transgene expression [112], and a retrograde approach successfully induced transgene expression in the renal tubular epithelium in cortex and medulla using recombinant AAV serotype 2 [106,112]. For example, it was recently shown that injection of recombinant AAV serotype 9 in the murine renal vein is effective for renal transgene expression [112], and a retrograde approach successfully induced transgene expression in the renal tubular epithelium in cortex and medulla using recombinant AAV serotype 2 [106,112].…”