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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number7339
JournalNature communications
StatePublished - Jun 17 2015
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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