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Updated: Aug 6, 2026
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Precise hepatic base editing of ASGR1 enables robust and durable LDLR-independent lipid lowering in vivo
Yaofeng Hou1, Yaxin Luo1, Jiabei Chen1
1Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Insights
Gene therapy using ASGR1 base editing effectively lowers cholesterol in a mouse model of severe familial hypercholesterolemia (FH). This approach offers a promising, durable, and LDLR-independent treatment for homozygous FH (HoFH).
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Disease Research
Background:
- Familial hypercholesterolemia (FH) is an autosomal dominant disorder causing life-threatening cardiovascular disease, often due to LDLR variants.
- Therapeutic options for homozygous FH (HoFH) are limited, necessitating novel LDLR-independent gene therapies.
- ASGR1 loss-of-function variants are linked to reduced cholesterol and cardiovascular risk, but in vivo ASGR1 editing for HoFH remains unexplored.
Purpose of the Study:
- To investigate the therapeutic potential of in vivo ASGR1 base editing as an LDLR-independent gene therapy for severe HoFH.
- To establish a therapeutically relevant editing window for ASGR1 suppression.
- To compare ASGR1 editing with ANGPTL3 editing and explore combined editing strategies.
Main Methods:
- Utilized an optimized hepatocyte-specific delivery platform for ASGR1 base editing in Ldlr-/- mice.
- Achieved liver-wide ASGR1 base editing and measured hepatic ASGR1 expression.
- Quantified serum levels of LDL-C, total cholesterol (TC), and triglycerides, and assessed safety profiles.
Main Results:
- Achieved 57.6% liver-wide Asgr1 base editing, resulting in ~95% reduction in hepatic ASGR1 expression.
- Observed sustained 40-50% reductions in serum LDL-C, TC, and triglycerides with a favorable safety profile.
- Demonstrated that moderate Asgr1 editing (32.0%) with 58% protein suppression also yielded significant lipid lowering, defining a therapeutic window.
Conclusions:
- Hepatic ASGR1 base editing is a potent and durable gene therapy strategy for severe HoFH.
- This approach is independent of LDLR function, addressing a critical unmet need.
- Combined ASGR1 and ANGPTL3 editing may offer enhanced cholesterol-lowering benefits.
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-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.
