But University of Michigan cardiologist Sanjay Rajagopalan, M.D. says that related strategies now being tested hold the potential to fulfill expectations for the technique, called therapeutic angiogenesis, in the treatment of peripheral arterial disease, or PAD. Rajagopalan, a member of the U-M Cardiovascular Center, will present data April 1 at the American College of Cardiology's 52nd Annual Scientific Session.
PAD is brought on by a hardening and clogging of the leg's blood vessels that mirrors the well-known effects seen in the blood vessels of the heart. Both kinds of blockage are brought on in part by high cholesterol and high blood pressure.
PAD is a painful, often disabling condition that affects about 2 million Americans. Only one drug has ever been approved for PAD, and it doesn't work for all patients.
"The need for effective treatments for PAD is pressing," says Rajagopalan, "especially because early stages of the disease are often overlooked by people who mistakenly think their leg pain and fatigue are just a normal part of growing older. By the time they're diagnosed, the condition has often worsened to the point where they can no longer walk more than a few minutes without experiencing debilitating pain." More than 250,000 hospitalizations each year are attributed to PAD.
Rajagopalan was a principal investigator of the 105-patient RAVE trial, the largest-ever adenovirus gene transfer trial in PAD. Participants in the RAVE study were between the ages of 40 and 80, and had a level of disability from their PAD that was similar to patients with severe heart failure – two thirds had difficulty walking even half a city block. Some had diabetes. The trial concluded without showing a significant improvement in the walking ability of any study participants.
In the multi-center, double-blind, randomized, controlled Phase II trial, participants received either placebo or a one-time intramuscular injection of an inactivated cold virus (adenovirus) containing the gene for vascular endothelial growth factor (VEGF). The injections were targeted to the leg with the worst symptoms.
RAVE was designed to use the adenoviral vector to express the VEGF gene at the disease site, increasing the ability to spur growth of new blood vessels where needed. The study showed the approach caused no side effects.
But patients who received either a low-dose injection or a high-dose injection showed no significant difference in walking time from patients who received a placebo. There were also no differences among the groups in lower-leg blood pressures or quality of life indicators.
The patients' peak walking time was measured before they received a one-time set of 20 injections of the VEGF-expressing adenoviral vector, and at several times in the months after the injections. At 12 weeks, those who received the low and high dose injections could walk 1.6 and 1.5 minutes longer, respectively, in comparison with placebo patients, who could walk 1.7 minutes longer.
One interesting observation was that patients treated with placebo improved somewhat, reinforcing the need for double-blinded trial design when investigating new approaches so that definite statements on efficacy can be made.
The U-M, one of the world's pioneering institutions in gene therapy, has been involved in early clinical studies of adenoviral vector-based gene delivery of VEGF, and an approach that injects growth factors into the bloodstream.
The RAVE results parallel those of another PAD study that used injections of an alternative growth factor protein called FGF, for fibroblast growth factor. An important difference in RAVE was the unilateral delivery of the injection to patients with disease predominantly in one limb.
U-M teams are now testing techniques involving transcription factor approaches and progenitor cells in both coronary and peripheral artery disease.
Many effective drugs and surgical techniques have been developed for blocked heart arteries, but PAD treatments have lagged behind. So, PAD patients may be ideal for testing proof-of-concept approaches in the area of therapeutic angiogenesis, which seeks to encourage the growth of new blood vessels, and gene transfer, which aims to deliver genes to the cells affected by disease.
Both academic researchers and private industry have tried to respond to the needs of PAD patients by aggressively translating new treatment concepts from the basic science laboratory to clinical trials. Rajagopalan emphasizes the importance of involving academic researchers in clinical trials, to ensure scientific study design and rigorous evaluation of results.
"The public has heard quite a bit about these approaches in the years since the media reported first signs of success from pilot-phase and Phase I studies," says Rajagopalan. "It's important that we did these scientific Phase II studies so that we could learn more about safety and also critically evaluate efficacy. These results should help researchers working in this area in examining priorities and strategies."