In vivo base editing of Asgr1 reduces blood lipids in mice

May 27, 2026Molecular therapy : the journal of the American Society of Gene Therapy

Using gene editing on a liver protein lowers blood fat levels in mice

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Abstract

Adenine base editing achieved 54.7% editing efficiency of Asgr1 in mice, reducing total cholesterol and triglyceride levels.

Targeting Asgr1 led to significant decreases in serum and liver total cholesterol and triglyceride levels.
The editing effects were partly due to changes in how cholesterol is excreted in bile.
No liver injury occurred following the base editing of Asgr1 in vivo.
Combining Asgr1 base editing with the drug ezetimibe resulted in an additional reduction in total cholesterol levels.
In human liver cells, lipid nanoparticles delivered base editing of ASGR1 with over 91% efficiency, nearly knocking out the protein and significantly lowering cholesterol.

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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.