Gene therapy shows promise as treatment for diseased lower limbs at risk for amputation

New research suggests that gene therapy is a safe treatment method to explore in patients whose lower limbs are at risk for amputation because of poor circulation caused by blocked blood vessels.

In a Phase I clinical trial, almost half the patients receiving gene therapy reported complete resolution of chronic pain one year after treatment and more than a quarter of patients with chronic wounds experienced complete healing of those ulcers in the same time frame. The results appear online and are scheduled for publication in the March 13 issue of the journal Circulation.

The researchers are the first to report on testing of the effects of the hypoxia-inducible factor-1 alpha (HIF-1a) gene as the basis of treatment for limbs damaged by compromised blood flow. Though the trial largely focused on the therapy's safety, "the bottom line is that 34 patients improved to varying degrees with this treatment," said Dr. Sanjay Rajagopalan, section director of vascular medicine at Ohio State University Medical Center and first author of the Circulation article.

The treatment is currently being tested in a major Phase II clinical trial in the United States and Europe.

"If this gene therapy approach were to prove safe and effective after exhaustive testing in Phase III studies, it would provide clinicians with an alternative approach to treating patients with serious blood flow problems in their lower limbs," Rajagopalan said.

Physicians are seeking better options to treat what is called critical limb ischemia because the condition often results in amputation and is characterized by chronic wounds that resist healing. The compromised blood flow is caused by severe blockages of peripheral arteries, or peripheral arterial disease (PAD), which occurs when cholesterol or plaque builds up in the arteries outside the heart - typically in the legs or pelvis. The one-year mortality rate in patients with critical limb ischemia is between 25 percent and 45 percent, and the risk of death increases with amputation.

An estimated 3 percent of Americans younger than age 60 have some degree of PAD, although they may not be aware of it because the early symptoms are often subtle. The frequency of the disorder increases with age, with more than 20 percent of individuals older than age 70 suffering from some form of it.

The current standard of care for critical limb ischemia includes the use of stents or balloons or bypass grafting to improve blood flow for patients who can tolerate such procedures. For many, these treatments offer only short-term benefits.

HIF-1a is considered a "master switch" gene produced naturally in the body that triggers the growth of blood vessel cells in patients with critical limb ischemia. The study drug, Ad2/HIF-1a/VP16, is a genetically modified form of the gene, intended to boost its active properties. The scientists theorized that HIF-1a may normalize oxygen levels in the cells by increasing interactions among multiple cytokines and genes that contribute to cell growth and facilitate survival of tissue damaged by reduced blood flow.

"Previous attempts to test gene-based formulations for critical limb ischemia have been disappointing, and that could be because the formulations tested were all single modality approaches that simply did not have the ability to induce the coordinated series of events required to induce vessel growth," said Rajagopalan, also associate director of vascular research for Ohio State's Davis Heart and Lung Research Institute.

He and colleagues administered the therapy through injections into the damaged limbs. The researchers completed two studies - a randomized, double-blind, placebo-controlled study, as well as an extension study in which participants, including some who had been receiving placebo, received the active treatment. Patients enrolled at five U.S. centers had at least one main artery with complete or nearly complete blockage and no other options to fix the vessels.

Though 21 of 38 patients completing the trials experienced adverse effects, all negative events were attributed to their illness and not the study treatment. Because the study group was small, no effect was attributed to different doses of the therapy.

At one year, 14 of 32 patients experienced complete resolution of pain while at rest, and five of 18 patients reported complete healing of chronic wounds. Other benefits included an increase in the number and size of visible vessels in affected legs.

Repeat administration of the study treatment is not considered an option because the body typically generates an immune response to gene therapy.

The study also confirmed the high rate of disease progression in patients with advanced circulation problems even with the study treatment. One year after the study began, 26 percent of all participating patients experienced amputation and 13 percent of patients died; of those receiving the study therapy, 29 percent experienced amputation and 9 percent died.