Base editing enables the precise, permanent modulation of gene expression, offering a promising therapeutic avenue for targeting lipid-regulating genes. Recently, asialoglycoprotein receptor 1 (ASGR1), a liver-specific receptor, has emerged as a potential therapeutic target for the control of circulating lipid levels. Here we employed adeno-associated virus serotype 8 (AAV8) to deliver an all-in-one adenine base editor (ABE) to target Asgr1 in mice. Systemic administration of Asgr1-targeting ABE achieved 54.7 ± 2.2% editing efficiency, leading to a marked depletion of hepatic ASGR1 and significant reductions in serum and hepatic total cholesterol (TC) and triglyceride (TG). These effects were mediated, in part, by the modulation of biliary cholesterol excretion pathways. No overt liver injury was observed following in vivo base editing of Asgr1. Moreover, combined treatment with Asgr1 base editing and the lipid-lowering drug ezetimibe produced an additive reduction in TC levels. Finally, lipid nanoparticles (LNPs)-delivered base editing of ASGR1 in human HepG2 cells achieved >91% editing, near-complete protein knockout, which significantly lowered cellular cholesterol. Collectively, our results demonstrate that ASGR1 base editing represents a promising strategy for blood lipid control.
CRISPR Gene Editing