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 and Karl-Dimiter Bissig ()
Additional contact information
Beatrice Bissig-Choisat: Center for Cell and Gene Therapy, Baylor College of Medicine
Lili Wang: Gene Therapy Program, University of Pennsylvania
Xavier Legras: Center for Cell and Gene Therapy, Baylor College of Medicine
Pradip K. Saha: Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, Baylor College of Medicine
Leon Chen: Center for Cell and Gene Therapy, Baylor College of Medicine
Peter Bell: Gene Therapy Program, University of Pennsylvania
Francis P. Pankowicz: Center for Cell and Gene Therapy, Baylor College of Medicine
Matthew C. Hill: Center for Cell and Gene Therapy, Baylor College of Medicine
Mercedes Barzi: Center for Cell and Gene Therapy, Baylor College of Medicine
Claudia Kettlun Leyton: Center for Cell and Gene Therapy, Baylor College of Medicine
Hon-Chiu Eastwood Leung: Department of Pediatrics, Department of Molecular and Cellular Biology
Robert L. Kruse: Center for Cell and Gene Therapy, Baylor College of Medicine
Ryan W. Himes: Texas Children’s Hospital
John A. Goss: Texas Children’s Hospital
James M. Wilson: Gene Therapy Program, University of Pennsylvania
Lawrence Chan: Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, Baylor College of Medicine
William R. Lagor: Baylor College of Medicine
Karl-Dimiter Bissig: Center for Cell and Gene Therapy, Baylor College of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms8339

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