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Improved animal models for testing gene therapy for atherosclerosis.

Liang Du1, Jingwan Zhang, Guido R Y De Meyer

  • 11 Division of Cardiology, Department of Medicine, University of Washington , Seattle, WA 98195.

Human Gene Therapy Methods
|February 18, 2014
PubMed
Summary

New rabbit models accelerate gene therapy research for atherosclerosis. These models enable rapid testing of vessel-wall gene therapies to prevent or reverse artery disease, advancing potential treatments.

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Area of Science:

  • Cardiovascular Biology
  • Gene Therapy
  • Animal Models

Background:

  • Atherosclerosis treatments like drug therapy and stenting can be improved with gene therapy.
  • Developing effective gene therapy requires clinically useful vectors and transgenes, currently in preclinical stages.
  • Animal models for testing vessel-wall gene therapy are needed for rapid, practical evaluation.

Purpose of the Study:

  • To develop new rabbit models for testing vessel-wall-directed gene therapy for atherosclerosis.
  • To create models that mimic human atherosclerosis development and lesion characteristics.
  • To enable testing of gene therapies aimed at preventing atherosclerosis or promoting lesion regression.

Main Methods:

  • Developed three new rabbit models with rapidly developing carotid artery intimal lesions (2-7 months) on a high-fat diet.

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  • Lesions were 20-80 times larger than in previous models, with specific models enriched in macrophages or smooth muscle cells.
  • Two models target gene delivery to normal arteries for prevention studies; one model targets existing lesions for regression studies.

    • Main Results:

    • The new models successfully generated significant atherosclerotic lesions in rabbits.
    • Models allow for targeted gene therapy testing in specific cell types (macrophages, smooth muscle cells).
    • Helper-dependent adenovirus (HDAd)-mediated gene therapy showed potential for long-term vascular endothelium therapy without accelerating disease.

    Conclusions:

    • The developed rabbit models are effective for preclinical testing of vessel-wall gene therapy for atherosclerosis.
    • These models facilitate the identification of strategies to prevent lesion development and promote lesion regression.
    • The models support the use of helper-dependent adenovirus for long-term gene therapy in vascular endothelium.