Distinct Pharmacokinetics of AAV9 and AAVKP1 Enable Context-Dependent Efficient Renal Transduction
- Pharmacology: Kinetics, Genomics, Medication-Related Problems
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- Furusho, Taisuke, Oregon Health & Science University, Portland, Oregon, United States
- Galbraith-Liss, Mia S., Oregon Health & Science University, Portland, Oregon, United States
- Sairavi, Anusha, Oregon Health & Science University, Portland, Oregon, United States
- Das, Ranjan, Oregon Health & Science University, Portland, Oregon, United States
- Nakai, Hiroyuki, Oregon Health & Science University, Portland, Oregon, United States
Recent progress in capsid engineering led to generation of numerous adeno-associated virus (AAV) vectors with novel phenotypes. However, they have not been evaluated in the context of renal gene transfer. Increased permeability of glomerular and peritubular capillary (PTC) is a common feature of CKD, but renal transduction in CKD kidney is yet to be characterized.
Renal transduction of 47 different AAV vectors following IV and renal vein (RV) administration was evaluated in C57BL/6J mice using NGS-based high-throughput method called AAV Barcode-Seq. Effect of CKD on renal transduction was assessed in X-linked Alport syndrome model mice. Select AAV vectors were individually vectorized and relationship between renal transduction and pharmacokinetics was evaluated.
AAV Barcode-Seq followed by individual characterization revealed that proximal tubule (PT) and podocyte transduction is not attainable by IV administration of AAV vectors. On the other hand, AAVKP1 but not AAV9 transduced PT following RV administration. Assessment of injection path using fluorescent microspheres showed accumulation in the cortical interstitial space following RV administration. Interestingly, >10 times more AAVKP1 vectors were detected in the injected kidney ten minutes post RV administration compared to AAV9. These observations suggest that RV administration bypasses PTC and efficient interstitial retention of AAVKP1 enables PT transduction from basolateral side. In contrast to minimal urinary excretion of AAV vectors in healthy mice, excretion of AAV9 but not AAVKP1 was significantly increased in CKD mice by about 104 times following IV administration. Difference between AAV9 and AAVKP1 is explained by rapid blood clearance of AAVKP1 that shows >1000 times less blood concentration than AAV9 over eight hours post injection. Consistent with this observation, IV administration of AAV9 but not AAVKP1 achieved efficient podocyte and PT transduction in CKD kidney, suggesting that higher blood concentration of AAV9 facilitates access to podocytes and PT across leaky glomerular filtration barrier and PTC in CKD.
Our study underscores the important role of AAV pharmacokinetics in renal gene transfer. Appropriate selection of AAV vector depending on administration route and host condition is vital for successful gene therapy.