Precise hepatic base editing of ASGR1 enables robust and durable LDLR-independent lipid lowering in vivo.

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-cholesterol (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.