Efficient AAV8 delivery to the liver via isolated hepatic perfusion and analysis of hepatic lobule transduction patterns
10.1016/j.livres.2025.04.006
- Author:
Chao Wang
;
Mingming Fan
;
Jianrong Liu
;
Xiaolu Guo
;
Zhipeng Tan
;
Xueying Huang
;
Zhuoran Li
;
Xiaomei Liu
;
Ye Zhang
;
Jianqi Feng
;
Rui Fang
;
Li Wang
;
Qiong Ke
- Publication Type:Journal Article
- From:
Liver Research
2025;9(4):313-323
- CountryChina
- Language:English
-
Abstract:
Background and aims
Adeno-associated virus (AAV) is becoming an attractive vector due to its low toxicity and minimal immunogenicity. However, liver-targeted AAV gene therapy still faces challenges, such as low delivery efficiency and safety risks associated with high vector doses. Isolated hepatic perfusion (IHP) has been explored as a localized drug delivery method, yet its full potential in gene therapy remains under investigation. Here, we investigated the efficiency of AAV8 delivery via the IHP route and its preference for hepatic transduction.
Methods
The IHP route was established through surgery in rats and cynomolgus monkey, and the AAV8-dTomato solution was injected into the entire liver through the inflow tract and maintained for 10 min. One week later, liver tissues were obtained, and the dTomato fluorescence expression area fraction and intensity were analyzed.
Results
AAV8-dTomato delivery via the IHP resulted in over 60% dTomato-positive areas in rat liver and showed higher efficiency than the portal vein (PV) and inferior vena cava (IVC) routes at equivalent doses. In rats, AAV8-dTomato expression was primarily periportal across IHP, PV, and IVC routes, while in cynomolgus monkey, IHP delivery showed a pericentral pattern.
Conclusions
In this study, we found that IHP is an effective strategy for AAV8 delivery. In addition, the distribution characteristics of AAV8, when delivered in cynomolgus monkey via IHP, provide candidate vector delivery schemes for gene therapy for different types of genetic liver diseases.
