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Nat Commun. 2015 Jun 17;6:7339. doi: 10.1038/ncomms8339.

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

Author information

1
Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
2
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Diabetes and Endocrinology Research Center, Baylor College of Medicine, Houston, Texas 77030, USA.
4
1] Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Molecular and Cellular Biology Graduate Program, Baylor College of Medicine, Houston, Texas 77030, USA.
5
1] Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
6
1] Department of Pediatrics, Department of Molecular and Cellular Biology, Houston, Texas 77030, USA [2] Dan L. Duncan Cancer Center, and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
7
1] Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, Texas 77030, USA.
8
Department of Pediatrics, Texas Children's Hospital, Houston, Texas 77030, USA.
9
Department of Surgery, Texas Children's Hospital, Houston, Texas 77030, USA.
10
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
11
1] Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Dan L. Duncan Cancer Center, and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.

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.

Comment in

PMID:
26081744
PMCID:
PMC4557302
DOI:
10.1038/ncomms8339
[Indexed for MEDLINE]
Free PMC Article

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