Low-density lipoprotein receptor gene therapy using helper-dependent adenovirus produces long-term protection against atherosclerosis in a mouse model of familial hypercholesterolemia

Gene Ther. 2004 Oct;11(20):1540-8. doi: 10.1038/sj.gt.3302310.

Abstract

We tested the efficacy of low-density lipoprotein receptor (LDLR) therapy using helper-dependent adenovirus (HD-Ad), comparing it with that of very low-density lipoprotein receptor (VLDLR), an LDLR homolog. We treated high cholesterol diet fed LDLR-/- mice with a single intravenous injection of HD-Ad expressing monkey LDLR (1.5 x 10(13) or 5 x 10(12) VP/kg) or VLDLR. Throughout the 24-week experiment, plasma cholesterol of LDLR-treated mice was lower than that of VLDLR-treated mice, which was in turn lower than that of PBS-treated mice. Anti-LDLR antibodies developed in 2/10 mice treated with high-dose HD-Ad-LDLR but in none (0/14) of the other treatment groups. HD-Ad-treated mice displayed significant retardation of atherosclerotic lesion progression. We next tested the long-term efficacy of low-dose HD-Ad-LDLR injected into 12-week-old LDLR-/- mice. After 60 weeks, atherosclerosis lesions covered approximately 50% of the surface of aortas of control mice, whereas aortas of treated mice were essentially lesion-free. The lipid lowering effect of HD-Ad-LDLR lasted at least 108 weeks (>2 years) when all control mice had died. In addition to retarding lesion progression, treatment caused lesion remodeling from a vulnerable-looking to a more stable-appearing phenotype. In conclusion, HD-Ad-mediated LDLR gene therapy is effective in conferring long-term protection against atherosclerosis in a mouse model of familial hypercholesterolemia.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / immunology
  • Animals
  • Arteriosclerosis / prevention & control*
  • Base Sequence
  • Disease Progression
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Hyperlipoproteinemia Type II / immunology
  • Hyperlipoproteinemia Type II / metabolism
  • Hyperlipoproteinemia Type II / therapy*
  • Mice
  • Mice, Knockout
  • Models, Animal
  • Molecular Sequence Data
  • Receptors, LDL / genetics*
  • Receptors, LDL / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology
  • Time Factors
  • Transduction, Genetic / methods*

Substances

  • Receptors, LDL
  • VLDL receptor