Gene therapy might keep arteries open

In their quest to unclog America’s arteries, cardiologists took a leap forward this month by showing they could deliver genes into arterial cells. This advance is one of a series that may boost the success rate of angioplasties, procedures that physically unblock coronary arteries.

Stent without (left) and with (right) DNA-polymer coating (red). Levy, et al./Nature Biotechnology

Green-fluorescent-marker genes released from a polymer-coated stent have penetrated a pig’s arterial cells. Levy, et al./Nature Biotechnology

The research builds on stents, tiny tubes of steel mesh permanently inserted after an angioplasty to hold a blood vessel open. Although stents help keep the arteries of many patients clear, in other cases, cells grow over the steel and reblock the artery. Scientists have known that certain genes can prevent excess arterial-cell growth, but they’ve been stumped when it comes to delivering enough of those genes to the right spot.

Now, researchers at the University of Pennsylvania in Philadelphia have created a DNA-containing polymer to coat a stent, making the device itself a gene-delivery tool. Once the stent is inserted into an artery, the polymer begins to degrade, releasing DNA that travels into the blood vessel cells that press against the device. In the November Nature Biotechnology, the scientists show that their coated stent delivers enough genes into pig-artery cells to merit further development as a therapeutic tool for people.

“[This] is the first time someone’s been able to put DNA in a solid [form] on a vascular stent, deploy that stent, and have gene transfer take place,” says cardiologist Robert J. Levy, who led the study. His group has taken the lead in a crowded field of bioengineers competing to deliver genes from a polymer-coated stent.

The Penn team has an elegant solution to a problem that scientists have been trying to tackle for years, says molecular biologist Ken Walsh at Tufts University in Medford, Mass. The work is generating a lot of interest in industry as well, adds Walsh, whose group is independently developing gene-delivery stents. The market for coronary stents worldwide has been estimated at $2.4 billion.

“Competition in this area is hot,” says James J. Barry, vice president of technology development at Boston Scientific in Natick, Mass. “Drug-coated stents are the biggest topic in interventional cardiovascular treatment.” Boston Scientific is in the midst of clinical trials on a polymer-coated stent designed to deliver a chemotherapy agent but not genes.

The polymer in Levy’s experiment did not contain a therapeutic gene. That will come later, he says. Instead, the stent coating harbored an easily detectable marker gene to help the scientists see which cells picked up DNA. Of the DNA that penetrated cells, most went into the arterial walls but traces turned up in certain lung cells.

Previous studies had found that the polymer can cause serious inflammation in arteries after 4 weeks of contact. Levy’s group says it may be able to quell that problem by including an anti-inflammatory gene in the polymer. Alternatively, a layer of collagen—the protein that tendons are made of—might be used to tether gene-delivering viruses to the device.

To reach the ultimate goal of reducing cell buildup around stents, Levy’s group has begun to select a therapeutic gene, or several of them, to replace the marker. He says his team hopes to start an animal study in January to determine a safe dosage of therapeutic DNA.

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