Silencing hepatic PCSK9 via novel chimeric AAV8 mitigates the progression of atherosclerosis by inhibiting inflammation in ApoE^-/- mice.

ABSTRACT: Adeno-associated virus (AAV) is the most widely utilized vector for gene therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9), predominantly expressed in the liver, plays a crucial role in lipid regulation and atherosclerosis progression. Here, we developed a novel chimeric AAV8.P-PCSK9 short hairpin RNA (shRNA) vector that incorporates a cross-species specific shRNA targeting PCSK9 to assess its effects on lipid levels and atherosclerosis in mice. AAV8.P demonstrated superior transduction efficiency and safety, achieving about 90% liver transduction and maintaining transgene expression for up to a year. The AAV8.P-PCSK9 shRNA exhibited typical liver-tropism and effectively silenced hepatic PCSK9. Moreover, it significantly lowered serum cholesterol and triglyceride levels while

SUBMITTER: Chen X 

PROVIDER: S-EPMC11787523 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature