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Large Animal Model for Evaluating the Efficacy of the Gene Therapy in Ischemic Heart
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Large Animal Model for Evaluating the Efficacy of the Gene Therapy in Ischemic Heart

Published on: September 2, 2021

Anti-inflammatory gene therapy for cardiovascular disease

Tetsuya Matoba1, Kensuke Egashira

  • 1Department of Cardiovascular Medicine, Kyushu University Graduate, School of Medical Sciences, Fukuoka, Japan.

Current Gene Therapy
|October 26, 2011
PubMed

Insights

Gene therapy using a modified monocyte chemoattractant protein-1 (MCP-1) variant (7ND) effectively reduced inflammation and lesion formation in atherosclerosis models. This approach, delivered via gene-eluting stents and nanoparticles, shows promise for cardiovascular disease treatment.

Area of Science:

  • Cardiovascular Research
  • Gene Therapy
  • Immunology

Background:

  • Atherosclerosis development involves vascular wall inflammation, primarily driven by infiltrating monocytes/macrophages.
  • Monocyte chemoattractant protein-1 (MCP-1) and its receptor CC chemokine receptor 2 (CCR2) are key mediators of this inflammatory process.
  • Targeting the MCP-1/CCR2 pathway offers a potential therapeutic strategy for atherosclerosis.

Purpose of the Study:

  • To evaluate the therapeutic potential of a dominant-negative MCP-1 mutant (7ND) for inhibiting monocyte/macrophage-mediated inflammation in atherosclerosis.
  • To assess the efficacy of 7ND gene therapy delivered via gene-eluting stents and nanoparticle systems.
  • To explore the application of 7ND gene therapy for treating atherosclerotic cardiovascular diseases.

Main Methods:

  • Development of a 7ND mutant MCP-1 that inhibits native MCP-1 activity via dominant-negative effect.
  • In vivo gene therapy using intramuscular transfection of 7ND plasmid in hypercholesterolemic mice and vascular injury models.
  • Coating bare metal stents with 7ND plasmid-loaded polymer for gene delivery in rabbit and monkey models.
  • Encapsulation of 7ND plasmid in polymer nanoparticles (NPs) for targeted gene delivery.

Main Results:

  • 7ND gene therapy demonstrated significant inhibition of atherosclerosis and neointima formation in preclinical models.
  • 7ND-eluting stents successfully reduced macrophage infiltration and in-stent neointima formation in animal arteries.
  • NP-mediated 7ND gene delivery effectively inhibited MCP-1-induced macrophage chemotaxis ex vivo.

Conclusions:

  • Anti-inflammatory gene therapy targeting the MCP-1/CCR2 pathway using the 7ND mutant is a viable strategy for atherosclerosis.
  • Novel delivery systems, including gene-eluting stents and nanoparticle-based gene delivery, enhance therapeutic efficacy.
  • This approach holds significant promise for the treatment of cardiovascular diseases driven by inflammation.

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