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

Bissig-Choisat B1, Wang L2, Legras X1, Saha PK3, Chen L1, Bell P2, Pankowicz FP4, Hill MC5, Barzi M1, Kettlun Leyton C1, Leung HC6, Kruse RL7, Himes RW8, Goss JA9, Wilson JM2, Chan L3, Lagor WR10, Bissig KD11
Source: Nat Commun.
Publication Date: (2015)
Issue: 6(7339: 1038
Cells used in publication:
Hepatocyte, human
Species: human
Tissue Origin: liver
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.