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Media Contact: Denine Hagen
Telephone: 619-534-2920
FAX: 619-822-1009
Email: dhagen@ucsd.edu

GENE THERAPY HELPS PREVENT OCCURANCE OF CLOGGED ARTERIES FOLLOWING BALLOON ANGIOPLASTY IN UC SAN DIEGO LABORATORY STUDIES

Approximately one-third of all patients who receive balloon angioplasty to clear clogged arteries experience a recurrence of the clogging, a condition known as restenosis, within weeks or months following treatment. An experimental genetic therapy reduced restenosis by 75 percent in animal trials, according to bioengineering researchers at the University of California, San Diego (UC San Diego) School of Engineering.

The research will be presented in a poster session at the Biomedical Engineering Society annual fall meeting on Saturday, October 4 in San Diego.

"One of the benefits of this treatment is that it can be given through the catheter during angioplasty. In this way, the treatment does not require additional invasive procedures and the localized delivery of the therapeutic agent avoids potential complications caused by action elsewhere in the body," said Shu Chien, professor and chair of bioengineering at UC San Diego School of Engineering and principal investigator on the study.

Atherosclerosis in coronary arteries can lead to heart attack, and angioplasty is a common treatment to remove this dangerous artery-clogging plaque. A catheter is inserted into the artery and inflated to press against the artery wall. However, this treatment can damage the endothelium, which is the lining of the artery wall. The endothelium may be rubbed away, exposing an inner layer of smooth muscle cells. In response to this injury and exposure to chemical signals that would not normally reach the interior wall, the smooth muscle cells grow, forming a thick lining in the artery wall. This new bump in the wall changes the fluid mechanics of blood flow and causes a turbulent, eddy motion in blood flow downstream from the thick and narrowed section of the artery.

Chien and his colleagues have previously found that such force generated by blood flow, called shear stress, turns on the MCP-1 gene within the endothelial cells. The MCP-1 gene, in turn, activates a protein, which attracts white blood cells called monocytes and allows the cells to enter the artery wall. At the same time, the eddy flow speeds up the life cycle of endothelial cells. As they grow, divide and die off, gaps are opened between the endothelial cells, making way for low density lipoproteins (LDL) to slip into the artery wall. Once monocytes and LDL hook up, the ball is in motion for the reformation of artery-clogging plaque.

Chien has mapped the chain of molecular players that lead to the activation of the MCP-1 gene in the nucleus of endothelial cells. He has also found that the signal pathways that mediate the mechanical forces are similar to those initiated by chemical factors such as cytokines released during inflammation. The RAS protein, found near the endothelial cell surface, is one of the key players in this signaling pathway.

Chien's gene therapy technique uses RASN17, a negative mutant of RAS that blocks the signaling pathway.

During the experiment, rats received a surgery similar to angioplasty. One section of the rats' damaged arteries was treated with RASN17, while another section was untreated. Chien found that the treated arteries developed a remarkably reduced wall thickening, which was only about 25 percent of that of the untreated arteries; thus there was a 75 percent reduction in the atherosclerotic response and restenosis.

Chien is continuing these studies to try to achieve a stronger prevention of restenosis. He and his colleagues are varying the duration and dosage of the RASN17 treatment; and they are combining other genes that block the signaling pathway into a cocktail therapy.


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