7.1 Kidney tissue structure
Barrier differences in glomeruli, proximal/distal tubules, collecting ducts, and interstitial cells make the results of systemic administration highly heterogeneous.
7.2 AAV serotype selection
The effects of AAV9 and AAV2/8 vary depending on the route and cells; local renal vein or retrograde ureter is often better than simple systemic exposure.
7.3 Kidney-specific promoter
NPHS1/2 is used in podocytes, CDH16 is used in renal tubules, and AQP2 is used in collecting duct-related design.
7.4 Administration method and dosage reference
Renal vein injection: one of the best routes for kidney targeting. Mouse 1×10^11-1×10^12 vg/kidney (about half of the tail vein dose), 100 μL, 30-31 G needle, open the abdomen and microscopically clamp the renal artery and vein, inject slowly through the proximal end of the renal vein, remove the needle for compression after about 5 seconds; transduce the renal tubular epithelium and glomerular cells, the liver off-target is significantly lower than the tail vein, and detected in 2-4 weeks [7-3].
Retrograde ureteral injection: full nephron segment coverage. Mouse 1×10^11 vg/kidney, about 100 μL, puncture the ureter with a 33 G needle, clamp the renal artery for 30 minutes to maximize exposure, and inject slowly retrogradely at about 50-100 μL/min; transduce proximal tubules, distal tubules, collecting ducts, and podocytes, and cooperate with segment-specific promoters such as SGLT2/NKCC2/ECAD to achieve segment-specific expression; extrarenal expression is minimal [7-1].
Systemic administration: The renal transduction efficiency is low, 1×10^11-1×10^12 vg/animal. Rat 1×10^11-5×10^11 vg/kidney, 100-200 μL; NHP data limited. Renal tissue vg, target cell expression, and urine/blood function indicators must be interpreted separately [7-4].
7.5 Key research evidence
Rocca et al. comparatively confirmed that rAAV9 combined with renal vein injection is the optimal solution for kidney-targeted gene delivery [7-3]; Asico et al. achieved nephron segment-specific AAV gene expression [7-1]; Lee et al. compared the renal gene delivery efficiency of adenovirus/AAV/lentivirus via intravenous and direct renal injection [7-4].
7.6 References for this chapter
[7-1] Asico LD, et al. Nephron segment-specific gene expression using AAV vectors. Biochem Biophys Res Commun. 2018;497:19-24. [H]
[7-2] Lake BB, et al. An atlas of healthy and injured cell states and niches in the human kidney. Nature. 2023. [N/H]
[7-3] Rocca CJ, et al. rAAV9 with renal vein injection for kidney-targeted delivery. Gene Ther. 2014;21:618-628. [F]
[7-4] Lee PY, et al. Comparison of gene delivery to the kidney by adenovirus, AAV, and lentiviral vectors after intravenous and direct kidney injections. Hum Gene Ther. 2020;31:463-477. PMC6919283. [H]