06 February 2006

Gene Therapy Poised for Widespread Use in Metal Implants

Metallic artery stents are routinely used to open clogged coronary arteries. One of the major problems with stents is the frequency of restenosis. Now, scientists have proven that genetic therapy can be administered by way of the stent, to cut down on restenosis.
This medical news today article describes research from the Children's Hospital of Philadelphia, where a team of cardiologists and scientists demonstrated the technique both in cell culture and in rodents.

Cardiologists frequently treat heart disease patients now by using stents to expand partially blocked blood vessels and improve blood flow. However, new obstructions may gradually form within the stents themselves and dangerously narrow the passageway. A newer generation of stents releases drugs to counteract this renarrowing process, called restenosis, but the polymer coatings that initially hold the drugs to the stents may stimulate inflammation. The inflammation in turn leads to restenosis.

Researchers at The Children's Hospital of Philadelphia have developed a novel technique to attach therapeutic genes to a stent's bare metal surface. This technique allows the genes to help heal the surrounding blood vessels, while avoiding the inflammation caused by polymer coatings.

The research team reported their proof-of-principle study, using cell culture and animal models, in the early edition of the Proceedings of the National Academy of Sciences, published online this week.

“This is the first study to demonstrate successful delivery of a gene vector from a bare metal surface,” said senior author Robert J. Levy, M.D., the William J. Rashkind Chair of Pediatric Cardiology at The Children's Hospital of Philadelphia. A gene vector is a biological substance, in this case an adenovirus, capable of delivering a therapeutic gene to target cells.

Dr. Levy's team created a unique water-soluble compound, polyallylamine biphosphonate, that binds to the stent's metal alloy surface in a layer with the thickness of only a single molecule. The biphosphonate holds and gradually releases adenovirus particles of the type used to deliver therapeutic genes.

In cell cultures, the adenovirus successfully delivered genes from alloy samples to animal arterial smooth muscle cells. In a second experiment using rodents, the researchers detected gene expression with significantly lower restenosis in the carotid arteries of animals with the experimental stents, compared to control animals with conventional, polymer-coated stents.

This procedure utilizes adenovirus as a vector to introduce the genes for inducible Nitric Oxide Synthetase into the vascular cells. Adenovirus gene vector has caused problems in human use in the past, but a lot of progress has been made recently, making the procedure safer. Even so, non-viral vectors for gene therapy in stents will likely follow in short order.

Here is an abstract describing gene therapy using artificial heart valve leaflets. Potentially, any implanted device which is prone to inflammatory reactions or other reactions could be used for gene therapy. Given the increasing use of artificial implants in medicine, the widespread use of gene therapy cannot be far off.
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