Temporary amelioration of hyperlipidemia in low density lipoprotein receptor-deficient rabbits transplanted with genetically modified hepatocytes

James M. Wilson, N. Roy Chowdhury, Mariann Grossman, Renata Wajsman, Adam Epstein, Richard C. Mulligan, Jayanta Roy-Chowdhury

Research output: Contribution to journalArticle

110 Citations (Scopus)

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 (VVHHL) 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.

Original languageEnglish (US)
Pages (from-to)8437-8441
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume87
Issue number21
StatePublished - 1990
Externally publishedYes

Fingerprint

Hyperlipoproteinemia Type II
LDL Receptors
Hyperlipidemias
Hepatocytes
Rabbits
Liver
Transplantation
Proviruses
DNA Viruses
Retroviridae
Portal Vein
LDL Lipoproteins
Genetic Therapy
In Situ Hybridization
Coronary Artery Disease
Animal Models
Cholesterol
Serum
Population
Genes

Keywords

  • Familial hypercholesterolemia
  • Gene therapy
  • Hepatocyte transplantation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Temporary amelioration of hyperlipidemia in low density lipoprotein receptor-deficient rabbits transplanted with genetically modified hepatocytes. / Wilson, James M.; Chowdhury, N. Roy; Grossman, Mariann; Wajsman, Renata; Epstein, Adam; Mulligan, Richard C.; Roy-Chowdhury, Jayanta.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 87, No. 21, 1990, p. 8437-8441.

Research output: Contribution to journalArticle

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