Gene Therapy Protects Against Atherosclerosis in Hyperlipidemic Rabbit Model

The gene for a protein that protects against atherosclerosis was implanted into the cells lining the arteries of a rabbit atherosclerosis model and prevented development of new arterial plaques while reducing the size of those already present.

Investigators at the University of Washington (Seattle, USA) worked with a population of hyperlipidemic rabbits that were prone to the formation of arterial plaques. Some of the animals were treated by an advanced gene therapy technique. Their carotid arteries were infused with an HDAd (helper-dependent adenovirus) viral vector that carried the gene for rabbit apo A-I. Apo A-I is the major protein component of HDL (high-density lipoproteins) and has been linked to removal of cholesterol from the arterial wall for processing by the liver. Other animals were treated with the HDAd vector that lacked the apo A-I gene.

Results published in the July 19, 2011, online edition of the journal Molecular Therapy revealed that apo A-I mRNA and protein were detected only in HDAd-Apo AI arteries. Lesion size, lipid and macrophage content, and adhesion molecule expression were similar in both groups at two weeks. Between two and four weeks, most of these measures of atherosclerosis increased in the arteries of the rabbits that received only the vector, but were stable or decreased in the arteries that had incorporated the apo A-I gene.

A longer-term study in chow-fed rabbits revealed that HDAd vector DNA and apo A-I expression persisted for more than 48 weeks, with stable vector DNA content and apo A-I expression from four to 48 weeks.

“Introducing into the blood vessel wall genes that protect against atherosclerosis is potentially an effective means of preventing or reversing plaque formation and inflammation,” said senior author Dr. David A. Dichek, professor of cardiovascular research at the University of Washington. “As applied in our study, the introduced genes can produce proteins that counteract the fundamental processes that drive atherosclerosis, including preventing lipid accumulation inside the artery wall and decreasing recruitment of inflammatory cells. We found both of these effects."

“Localized one-time gene therapy might someday be an alternative or an important adjunct to systemic drugs such as statins that patients take for decades,” said Dr. Dichek. “In gene-therapy trials for other diseases, one-time treatments have shown efficacy for at least nine years and will likely continue to be effective indefinitely. Because atherosclerosis is a life-long threat, gene therapy that protects blood vessels for a lifetime makes a lot of sense.”

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