Related Experiment Video
Updated: Jun 29, 2025
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Recapitulating familial hypercholesterolemia in a mouse model by knock-in patient-specific LDLR mutation
Insights
Familial hypercholesterolemia (FH) is a common genetic disorder causing cardiovascular disease. Adenine base editor (ABE) therapy shows promise for FH by correcting the Ldlr gene mutation in a new mouse model.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Disease Research
Background:
- Familial hypercholesterolemia (FH) is a prevalent monogenetic disorder leading to cardiovascular disease (CVD).
- Mutations in the Low-density lipoprotein receptor (Ldlr) gene are the primary cause of FH.
- Current treatments for FH lack efficacy and safety, necessitating novel therapeutic approaches.
Purpose of the Study:
- To develop a preclinical model for Familial hypercholesterolemia (FH) that accurately reflects human disease characteristics.
- To evaluate the potential of Adenine Base Editor (ABE)-mediated molecular therapy for treating FH.
- To address the translational gap between mouse models and human patients for ABE therapy.
Main Methods:
- Generation of a knock-in mouse model (LdlrW490X/W490X) harboring a patient-specific fragment with the Ldlr W490X mutation.
- Characterization of the mouse model for cholesterol metabolic disorder and atherosclerosis.
- In vitro validation of ABE-mediated repair of the mutant Ldlr gene in a cellular model.
Main Results:
- The LdlrW490X/W490X mice successfully recapitulated FH phenotypes, including elevated plasma low-density lipoprotein cholesterol and aortic lipid deposition.
- The developed mouse model mirrors the clinical manifestations of atherosclerosis observed in FH patients.
- ABE demonstrated efficacy in repairing the mutant Ldlr gene in the cellular model.
Conclusions:
- The LdlrW490X/W490X mouse model serves as a valuable preclinical tool for FH research.
- ABE-mediated molecular therapy holds significant promise for the future treatment of FH.
- These findings pave the way for the clinical application of ABE therapy in FH patients.
Abstract:
Familial hypercholesterolemia (FH) is one of the most prevalent monogenetic disorders leading to cardiovascular disease (CVD) worldwide. Mutations in Ldlr, encoding a membrane-spanning protein, account for the majority of FH cases. No effective and safe clinical treatments are available for FH. Adenine base editor (ABE)-mediated molecular therapy is a promising therapeutic strategy to treat genetic diseases caused by point mutations, with evidence of successful treatment in mouse disease models. However, due to the differences in the genomes between mice and humans, ABE with specific sgRNA, a key gene correction component, cannot be directly used to treat FH patients. Thus, we generated a knock-in mouse model harboring the partial patient-specific fragment and including the Ldlr W490X mutation. LdlrW490X/W490X mice recapitulated cholesterol metabolic disorder and clinical manifestations of atherosclerosis associated with FH patients, including high plasma low-density lipoprotein cholesterol levels and lipid deposition in aortic vessels. Additionally, we showed that the mutant Ldlr gene could be repaired using ABE with the cellular model. Taken together, these results pave the way for ABE-mediated molecular therapy for FH.
