Simini, Giulia;
Batty, Paul;
(2025)
The Hepatic Odyssey of AAV: From Gene Delivery to Long-Term Outcomes.
Journal of Thrombosis and Haemostasis
10.1016/j.jtha.2025.08.028.
(In press).
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Abstract
Adeno-associated virus (AAV) vectors are the most developed approach for in-vivo gene therapy. This treatment has resulted in therapeutically meaningful treatment responses for a range of monogenic inherited disorders, including hemophilia. Understanding the core stages in the lifecycle of AAV supports the shared decision-making process for clinicians and individuals considering gene therapy. These key steps start after vector infusion, including receptor engagement, cellular uptake, endosomal escape, nuclear entry, and transgene expression. All of these stages could influence transduction efficiency, which could result in differences in treatment outcomes between individuals. The natural history of how AAV persists in cells could provide insights into long term efficacy and safety. The immune system may also pose an obstacle to successful outcomes. Studies have shown that pre-existing immunity to natural AAV is common and may exclude some individuals from receiving gene therapy. Additionally, asymptomatic liver enzyme elevation which can result in loss of expression is an important area in which more research is required. Ongoing advances in vector engineering and a better understanding of host-pathogen interactions are helping to address these challenges. This review provides a primer on the hepatic lifecycle of AAV and an introduction to the cellular and immune processes involved in AAV transduction and persistence in the liver.
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