Bioengineers at the University of California, San Diego (UCSD) Jacobs School of Engineering have developed a gene therapy to prevent restenosis following angioplasty, and the University has recently been issued U.S. Patent # 6,335,010 for the invention. The experimental gene therapy reduced the formation of clogged arteries by more than one-half in large animal models.
"In some sense, the procedure of angioplasty is tailor-made for delivering gene therapy,” said Shu Chien, university professor of bioengineering and medicine, and director of the Whitaker Institute of Biomedical Engineering at UCSD. “The therapeutic genes can be given through the catheter during angioplasty, so no additional invasive procedures are required. During angioplasty, the arteries being treated are clamped to reduce blood flow. By isolating the arteries in this way, it allows localized delivery of the therapeutic agent and avoids potential complications caused by action elsewhere in the body.”
Atherosclerosis in coronary arteries can lead to heart attack, and angioplasty is a common treatment to remove this dangerous artery-clogging plaque. However, one-third of all patients who receive balloon angioplasty experience a recurrence of the clogging, a condition known as restenosis, within weeks or months following treatment.
During angioplasty, 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 the underlying layer of smooth muscle cells to chemical agents in the blood and mechanical forces due to flow. In response to these chemical and mechanical stimuli, smooth muscle cells grow, forming a thick lining in the artery wall. This new bump in the wall causes a disturbance of blood flow pattern, with eddy motions and local flow reversal, which in turn activates a series of molecules that allow mononuclear white blood cells to enter the artery wall. At the same time, the disturbed 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 the white blood cells and LDL hook up, the ball is in motion for the reformation of artery-clogging plaque. Chien has found that the RAS protein is a pivotal player in the signaling pathway that attracts white blood cells to the region.
Chien's gene therapy technique uses RasN17, a negative mutant of RAS that blocks the signaling pathway. Chien’s animal studies have shown that by introducing RasN17 during the angioplasty procedure, the gene therapy can prevent restenosis. The action of the therapeutic gene can be directly targeted to the smooth muscle cells, because these cells are exposed by the angioplasty procedure.
Chien has tested the therapy in pigs because the porcine cardiovascular system is similar to that of humans. In his experiments, pigs received a balloon angioplasty procedure at the coronary artery. A subset of the pigs also received RasN17 via a catheter during the procedure. Those pigs which received RasN17 had 56 percent less artery wall thickening than pigs which received a placebo gene therapy.
Results of these experiments, which were conducted in collaboration with the China Medical College and Pig Research Institute in Taiwan, were reported in the May 2001 issue of the Journal of Surgical Research.
UCSD is currently negotiating the license of the technology to a company that would continue to develop the therapy in preparation for clinical trials.
Media Contact: Denine Hagen, dhagen@ucsd.edu, 858-534-2920