Development and rescue of human familial hypercholesterolaemia in a xenograft mouse model

作者：Bissig Choisat Beatrice; Wang Lili; Legras Xavier; Saha Pradip K; Chen Leon; Bell Peter; Pankowicz Francis P; Hill Matthew C; Barzi Mercedes; Leyton Claudia Kettlun; Leung Hon Chiu Eastwood; Kruse Robert L; Himes Ryan W; Goss John A; Wilson James M; Chan Lawrence; Lagor William R; Bissig Karl Dimiter^*

来源：Nature Communications, 2015, 6(1): 7339.

DOI：10.1038/ncomms8339

Diseases of lipid metabolism are a major cause of human morbidity, but no animal model entirely recapitulates human lipoprotein metabolism. Here we develop a xenograft mouse model using hepatocytes from a patient with familial hypercholesterolaemia caused by loss-of-function mutations in the low-density lipoprotein receptor (LDLR). Like familial hypercholesterolaemia patients, our familial hypercholesterolaemia liver chimeric mice develop hypercholesterolaemia and a 'humanized' serum profile, including expression of the emerging drug targets cholesteryl ester transfer protein and apolipoprotein (a), for which no genes exist in mice. We go on to replace the missing LDLR in familial hypercholesterolaemia liver chimeric mice using an adeno-associated virus 9-based gene therapy and restore normal lipoprotein profiles after administration of a single dose. Our study marks the first time a human metabolic disease is induced in an experimental animal model by human hepatocyte transplantation and treated by gene therapy. Such xenograft platforms offer the ability to validate human experimental therapies and may foster their rapid translation into the clinic.

• 出版日期2015-6