Gene therapy may boost success rate of balloon angioplasties

By inserting a custom-built, growth-limiting gene into animals with clogged arteries that were opened with balloon angioplasty, researchers at Chicago and at the University of Michigan have been able to prevent the rapid post-treatment proliferation of blood-vessel muscle cells, called restenosis, that causes more than one-third of all human angioplasties to fail. The research was directed by Jeffrey Leiden, Professor in Medicine and Section Chief of Cardiology.

The finding, demonstrated in two different animal models of human restenosis, is reported in the Jan. 27 issue of Science. The procedure may soon be applicable to humans.

The finding is the first report of successful cytostatic gene therapy in vivo. "Cytostatic" refers to the ability of the imported gene to prevent the rapid proliferation of cells without killing them.

"In vivo," in this context, means the genes are delivered directly to the target cells within the body, rather than the cells being removed for treatment in the laboratory and then returned to the patient.

The research not only sheds light on muscle-cell biology, but also unveils a novel approach to a common clinical problem. It demonstrates that therapy with an existing gene complex could prevent restenosis after angioplasty and suggests that the same gene may also be a valuable weapon against certain types of cancer.

In an estimated 30 to 50 percent of the half-million patients who undergo balloon angioplasty each year in the United States, the treatment provokes rapid growth of the smooth muscle cells that surround the blood vessel. These muscle cells tend to grow into the channel created by the balloon, reducing blood flow through the artery. For about half of those patients -- about 100,000 people annually -- the problems are severe enough to require additional, more-invasive therapy such as placement of stents within the artery or bypass surgery.

"Our study demonstrates that in two different models, tested in two different labs, this gene can block restenosis, preventing the cell growth that shuts these arteries," Leiden said. "By temporarily programming these muscle cells not to divide, we can keep these vessels open and prevent the failure of the angioplasty."

The researchers used a modified form of the retinoblastoma (Rb) gene, a tumor suppressor that serves as a brake on the rapid cell growth characteristic of cancer cells. Loss of the Rb gene allows the uncontrolled growth of several different tumors.

This growth-regulating gene was inserted into a specially made virus that carries the gene into the muscle cells that line the artery walls. The virus was introduced into the arteries through a special catheter at the time of angioplasty.

Many specialists in the field agree that this approach -- using growth-regulating genes to keep arteries open after angioplasty -- may be the first realistic cardiovascular application of gene therapy because it is not affected by one of the stickiest problems currently facing gene-based treatments. Implanted genes and the viruses used to ferry them into cells can trigger an immune response that shuts off the new genes within a few weeks. But since restenosis is a rapid process, occurring a few days after angioplasty, the therapeutic gene only needs to function for a week or two to keep the artery open.

In a thorough series of studies conducted in the laboratory and in vivo, Leiden and his colleagues demonstrated that the virus efficiently transports the Rb gene into the muscle cells that line blood vessels, that the gene is expressed at high levels within those cells, that it blocks rapid muscle-cell growth and prevents muscle cells from crowding into the arteries after angioplasty, and that this technique keeps the treated arteries open. Then they repeated the entire series using a different animal model of restenosis to make certain that the desired response was not specific to one species or model. They found no significant toxicity in either model studied.

Rb is one of several tumor-suppressor genes that may prove effective in preventing unregulated cell growth. Leiden's team has already begun to test other genes, alone and in combination with Rb, for their ability to rein in unwanted cell growth without causing cell death.

"It may be even more effective to use multiple checkpoints, like a series of roadblocks along the same highway," Leiden said.

In addition to Leiden, authors of this paper include Mark Chang, Eliav Barr, Jonathan Seltzer, Yue-Qim Jiang and Michael Parmacek of the University of Chicago and Gary Nabel and Elizabeth Nabel of the University of Michigan.