Can gene therapy treat peripheral arterial disease?

Patient has dreams of someday walking the 2,167-mile Appalachian Trail. But for now, the 64-year-old computer scientist from Mountain View can’t even walk around the block without feeling a knife-like pain stabbing into his calves. He’s dearly love to walk that trail. But for the past six years, the leg pain, often followed by numbness in his feet and ankles when he walks, has severely limited his mileage. When the pain sets in, he has to throw in the towel. This patient who was finally diagnosed last year with peripheral arterial disease, or PAD, a hardening of the arteries in the legs, is taking part in a gene therapy trial at Stanford to test an experimental new drug for the treatment of this often painful and debilitating disease. Researchers are seeking more volunteers who have either been diagnosed with PAD or are experiencing undiagnosed discomfort in the legs that occurs with exercise.

To improve the ability of a patient to walk is by improving the blood flow to their legs that will improve their lifestyle and their health, according to a professor of cardiovascular medicine who has specialized in studying PAD for more than 20 years. A common but often undiagnosed disorder, PAD affects 8 to 12 million people in the United States, many who go years assuming they’re suffering from arthritis or just the aches and pains of getting older before finally being diagnosed. Essentially, PAD is caused by a process similar to the one that causes heart disease. A buildup of fatty deposits along the walls of the arteries limits the supply of oxygenated blood to the arms or legs causing restricted use, fatigue and/or pain. But rarely do people connect these symptoms with the term "blocked arteries." Even doctors often don’t recognize PAD. The multi-center study will test the experimental drug, Ad2/HIF-1 alpha/VP16, which is designed to encourage the growth of healthy new blood vessels to improve circulation to the legs. A total of about 300 patients at 35 sites in the United States, England and Germany will take part in the study, which is sponsored by the biotechnology company.

To develop the experimental drug for this study, scientists used a gene transfer technique that packages the gene responsible for triggering proteins that grow new blood vessels into a modified version of the cold virus. After injection, this virus is designed to ferry the gene into the body’s cells where it triggers a process called "angiogenesis" – new blood vessel growth. We are just trying to encourage what is already a natural process. Although the body grows new blood vessels on its own to bypass diseased vessels, the size and number are not usually significant enough to alleviate the negative side effects of blockage. Researchers say they are taking particular care to explain the risks of volunteering to prospective participants, given the checkered history of gene therapy trials, most notably the death of a volunteer in a study in Pennsylvania in 1999. We have a much better understanding of potential adverse affects. Potential volunteers will be required to undergo a thorough evaluation before being accepted into the study. Researchers are "extensively screening" all applicants. Those with cancer or other disorders negatively affected by the growth of new blood vessels have been deemed ineligible as a safety precaution. The formation of new blood vessels is often associated with the growth of solid tumors.

Once accepted into the study, volunteers will have the new drug injected into the muscle at 20 sites on each leg, and then undergo treadmill testing over the next two years to see whether leg pain decreases while walking distances increase. One out of every four patients will receive a placebo. Varying doses of the drug will be administered to the others. It’s really a quality of life issue. People with PAD have less motivation, less energy and less enjoyment because of their limited walking. Although we do not yet know if this new drug will help patients, we believe this study is an important step. This is the second phase of a three-phase study. The first phase was successfully completed with 30 PAD patients in Boston. Participants must be between 40 to 80 years old.