title: Development and rescue of human familial hypercholesterolaemia in a xenograft mouse model.
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.
authors.affiliation: Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bissig-Choisat
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Legras
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Diabetes and Endocrinology Research Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Saha
authors.affiliation: Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Leon
authors.initials: L
authors.lastname: Chen
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.affiliation: Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Molecular and Cellular Biology Graduate Program, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Francis P
authors.initials: FP
authors.lastname: Pankowicz
authors.affiliation: Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Hill
authors.affiliation: Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Barzi
authors.affiliation: Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Claudia Kettlun
authors.initials: CK
authors.lastname: Leyton
authors.affiliation: Department of Pediatrics, Department of Molecular and Cellular Biology, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Hon-Chiu Eastwood
authors.initials: HE
authors.lastname: Leung
authors.affiliation: Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Kruse
authors.affiliation: Department of Pediatrics, Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Himes
authors.affiliation: Department of Surgery, Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Goss
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Diabetes and Endocrinology Research Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Lagor
authors.affiliation: Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Karl-Dimiter
authors.initials: KD
authors.lastname: Bissig
mesh_terms: D000818:Animals; D002648:Child; D000229:Dependovirus; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D022781:Hepatocytes / Q000637:transplantation; D064593:Heterografts; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D008074:Lipoproteins / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: C573412:LDLR protein, human; D008074:Lipoproteins; D011973:Receptors, LDL