Recapitulating familial hypercholesterolemia in a mouse model by knock-in patient-specific LDLR mutation

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 (Ldlr^W490X/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 Ldlr^W490X/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 Ldlr^W490X/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.