Patient-specific iPS Cells of Autosomal Recessive Hypercholesterolemia as a Platform for Disease Modeling and Personalized Medicine

Objective: Familial hypercholesterolemia (FH) is a common genetic disorder that results in elevated levels of low-density lipoprotein (LDL) at birth. Mutations in several genes can lead to autosomal dominant forms of FH. Autosomal Recessive Hypercholesterolemia (ARH) is another type of FH which is most closely resembles forms of homozygous FH. Different mutations located in the LDLRAP1 gene can cause ARH. The LDLRAP1 gene encodes the ARH adaptor protein that is required for clathrin mediated endocytosis of LDLR in hepatocytes. Consequently, ARH patients have high LDL concentrations (often > 400 mg/dL) and a high risk of coronary heart disease before the age of 30. Treatment options are suboptimal because therapies that work by increasing LDLR levels (eg, statins or bile acid–binding resins) are partially effective and patients often require LDL-apheresis. In this regard, human induced pluripotent stem cell (hiPSC), could be an ideal source for drug screening, toxicology, generation of disease models and eventually cell replacement therapy. This approach can determine the contribution of each individual’s genomic variations to cholesterol homeostasis and lipoprotein metabolism which can be valuable to determine efficient therapeutic agents.Approaches and Results: Clinical and biochemical characterizations on the patient confirmed familial hypercholesterolemia. The Next-Generation Sequencing (NGS) data, identified a novel pathogenic mutation in the ARH gene, confirmed by segregation analysis within the family. Then, patient-derived hiPS cell lines (ARH-hiPSCs) were generated from dermal fibroblasts of the patient and subsequently characterized. Differentiation of the ARH-hiPSCs toward hepatocyte-like cells can represent an ideal in vitro model for this metabolic disorder.Conclusion: ARH-hiPSCs derived hepatocytes can provide a valuable platform, which is crucial for understanding the pathophysiology and developing therapies for disease. Furthermore, personalized drug selection and dose finding based on genomic sequencing data can prevent cardiovascular disease.

Keywords:

Autosomal Recessive Hypercholesterolemia , Patient-specific iPSC , Personalized Medicine , Disease Modeling