Generation of a familial hypercholesterolemia model in non-human primate

Abstract

Familial hypercholesterolemia (FH) is an inherited autosomal dominant disorder that is associated with a high plasma level of low-density lipoprotein (LDL) cholesterol, leading to an increased risk of cardiovascular diseases. To develop basic and translational research on FH, we here generated an FH model in a non-human primate (cynomolgus monkeys) by deleting the LDL receptor (LDLR) gene using the genome editing technique. Six LDLR knockout (KO) monkeys were produced, all of which were confirmed to have mutations in the LDLR gene by sequence analysis. The levels of plasma cholesterol and triglyceride were quite high in the monkeys, and were similar to those in FH patients with homozygous mutations in the LDLR gene. In addition, periocular xanthoma was observed only 1 year after birth. Lipoprotein profile analysis showed that the plasma very low-density lipoprotein and LDL were elevated, while the plasma high density lipoprotein was decreased in LDLR KO monkeys. The LDLR KO monkeys were also strongly resistant to medications for hypercholesterolemia. Taken together, we successfully generated a non-human primate model of hypercholesterolemia in which the phenotype is similar to that of homozygous FH patients.

Surgical Treatment of Multiple Large Tuberous and Tendinous Xanthoma Secondary to Familial Hypercholesterolaemia: A Case Report

“…FH is an inherited autosomal dominant disorder with a raised LDL plasma level, so patients with FH have a high risk of xanthomas. 5 In this case, no obvious diseases affecting lipid metabolism such as liver and kidney diseases and diabetes were found by routine examination, and blood lipid tests showed significant increases in serum cholesterol, especially LDL level. In addition, the patient reported that her grandfather and father also had hypercholesterolemia.…”