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

Authors

Yaofeng Hou, Yaxin Luo, Jiabei Chen, Xindi Shang, Yan Chang, Xianfang Zhang, Yan Ding, Wenwen Zhao, Chengfeng Ding, Xuan Feng, Jia Chen, Jianfeng Li, Bei Yang

Published in

Molecular therapy : the journal of the American Society of Gene Therapy. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

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.

PMID:
42470100
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.

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