Beatrice Bissig-Choisat 1 , Lili Wang 2 , Xavier Legras 1 , Pradip K. Saha 3 , Leon Chen 1 , Peter Bell 2 , Francis P. Pankowicz 1 , 4 , Matthew C. Hill 1 , 5 , Mercedes Barzi 1 , Claudia Kettlun Leyton 1 , Hon-Chiu Eastwood Leung 6 , 7 , Robert L. Kruse 1 , 8 , Ryan W. Himes 9 , John A. Goss 10 , James M. Wilson 2 , Lawrence Chan 3 , William R. Lagor 11 , Karl-Dimiter Bissig a , 1 , 7
17 June 2015
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.
Familial hypercholesterolemia (FH) is a congenital disease associated with high plasma cholesterol levels. Here, the authors recapitulate FH in chimeric mice, in which livers are repopulated with hepatocytes from an FH patient, and successfully correct the disease using adenovirus-mediated gene therapy.