Molecular therapy : the journal of the American Society of Gene TherapyJul 18, 2026

Accurate liver gene editing of ASGR1 leads to strong and lasting cholesterol lowering without relying on LDL receptors

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 19, 2026

Abstract

A 57.6% liver-wide editing of Asgr1 in Ldlr^-/- mice resulted in approximately 95% reduction of hepatic ASGR1 expression.

Base editing of Asgr1 led to sustained reductions of 40-50% in serum LDL cholesterol, total cholesterol, and triglyceride levels.
Moderate Asgr1 editing (32.0%) with partial protein suppression (58%) resulted in significant and lasting lipid lowering.
Comparative analysis with Angptl3 editing showed similar reductions in LDL cholesterol and total cholesterol.
Combining Asgr1 and Angptl3 editing further enhanced serum cholesterol lowering effects.
These results highlight hepatic ASGR1 base editing as a promising gene therapy approach for treating severe familial hypercholesterolemia.

Simplified

Familial hypercholesterolemia (FH), most frequently caused by LDLR loss-of-function variants, is a common autosomal dominant disorder that leads to early-onset, life-threatening cardiovascular disease. Therapeutic options for LDLR-deficient homozygous FH (HoFH) are very limited, motivating the development of durable, effective, and LDLR-independent gene therapies. Human genetic studies have linked ASGR1 loss-of-function variants with low serum cholesterol levels and significantly reduced cardiovascular risk, yet in vivo ASGR1 editing has not been explored as a therapeutic strategy for HoFH. Here, using an optimized hepatocyte-specific delivery platform, we achieved 57.6% liver-wide Asgr1 base editing in Ldlr^-/- mice, yielding ∼95% reduction of hepatic ASGR1 expression and sustained 40-50% reductions in serum LDL-C, total cholesterol (TC), and triglyceride levels, with a favorable safety profile. Importantly, moderate Asgr1 editing (32.0%) with partial protein suppression (58%) also conferred significant and durable lipid lowering, thereby defining a therapeutically relevant editing window aligned with ASGR1 suppression level in carriers of ASGR1 loss-of-function variants. Benchmarking against Angptl3 editing revealed comparable reductions in LDL-C and TC, while combined Asgr1/Angptl3 editing further enhanced serum cholesterol lowering, suggesting potential benefits of combined editing. Together, these findings establish hepatic ASGR1 base editing as a potent, durable, and LDLR-independent gene therapy strategy for severe HoFH.