Gene therapy with novel adeno-associated virus vectors substantially diminishes atherosclerosis in a murine model of familial hypercholesterolemia

J Gene Med. 2004 Jun;6(6):663-72. doi: 10.1002/jgm.554.


Background: Familial hypercholesterolemia is an inherited disease caused by mutations in the LDL receptor gene leading to severe hypercholesterolemia and atherosclerosis. The LDL receptor is predominantly expressed in the liver, making it a preferred target organ for somatic gene therapy. We recently isolated a new family of vectors based on adeno-associated viruses (AAVs) isolated from nonhuman primates, which enable efficient and stable transgene expression following in vivo gene delivery to liver.

Methods: Traditional vectors based on AAV serotype 2 and two novel AAVs from nonhuman primates, serotypes AAV7 and AAV8, were produced encoding for the human LDL receptor. Vectors were injected into the portal veins of LDL receptor deficient mice that were fed a high-fat diet to achieve severe pretreatment hypercholesterolemia.

Results: Animals receiving the novel AAV vectors realized nearly complete normalization of serum lipids and failed to develop the severe atherosclerosis that characterized the untreated animals; the AAV2 vector constructs demonstrated partial lipid correction and only a modest improvement in atherosclerosis.

Conclusions: Using vectors based on novel nonhuman primate AAVs, which provide advantages in terms of efficiency, we were able to achieve a long-term correction of the metabolic defect in LDL receptor deficient mice.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Arteriosclerosis / etiology
  • Arteriosclerosis / genetics
  • Arteriosclerosis / therapy*
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Gene Expression Regulation
  • Genetic Therapy / methods*
  • Genetic Vectors / adverse effects
  • Genetic Vectors / pharmacology
  • Humans
  • Hyperlipoproteinemia Type II / complications
  • Hyperlipoproteinemia Type II / genetics
  • Hyperlipoproteinemia Type II / therapy
  • Lipid Metabolism
  • Liver / pathology
  • Liver / physiology
  • Mice
  • Mice, Inbred C57BL
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Toxicity Tests


  • Receptors, LDL