title: Temporary amelioration of hyperlipidemia in low density lipoprotein receptor-deficient rabbits transplanted with genetically modified hepatocytes.
abstract: Familial hypercholesterolemia is an inherited disease in humans that is associated with coronary artery disease and is caused by a deficiency of the receptor that mediates the internalization of low density lipoprotein (LDL). We have used an animal model for familial hypercholesterolemia, the Watanabe heritable hyperlipidemic (WHHL) rabbit, to design a therapeutic approach for this disease, which attempts to correct the hepatic defect in LDL receptor expression. Hepatocytes were harvested from WHHL rabbits, plated in primary cultures, and exposed to recombinant retroviruses capable of efficiently transferring a functional human LDL receptor gene. Genetically modified cells were harvested and infused into the portal vein of WHHL recipients, who were analyzed for metabolic consequences of human LDL receptor expression. Each animal exhibited a statistically significant decrease in total serum cholesterol 2-6 days after transplantation, with an eventual return to pretreatment levels. Proviral DNA sequences and virus-directed transcripts were detected in liver tissue 24 hr after transplantation. In situ hybridization demonstrated provirus expression in a small population of hepatocytes distributed in periportal sections of the liver. This study illustrates the potential of somatic gene therapy in ameliorating hyperlipidemia associated with familial hypercholesterolemia.
authors.affiliation: Department of Internal Medicine, Howard Hughes Medical Institute, University of Michigan, Ann Arbor 48109.
authors.forename: J M
authors.initials: JM
authors.lastname: Wilson
authors.forename: N R
authors.initials: NR
authors.lastname: Chowdhury
authors.forename: M
authors.initials: M
authors.lastname: Grossman
authors.forename: R
authors.initials: R
authors.lastname: Wajsman
authors.forename: A
authors.initials: A
authors.lastname: Epstein
authors.forename: R C
authors.initials: RC
authors.lastname: Mulligan
authors.forename: J R
authors.initials: JR
authors.lastname: Chowdhury
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000235:genetics / Q000601:surgery*; D008099:Liver / Q000166:cytology; D016031:Liver Transplantation; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D011817:Rabbits; D011973:Receptors, LDL / Q000235:genetics*; D014162:Transfection
chemical_list: D015345:Oligonucleotide Probes; D011973:Receptors, LDL; D002784:Cholesterol