Angiogenesis therapy successful for peripheral arterial disease

10/13/04

DURHAM, N.C. Duke University Medical Center researchers have shown that they can stimulate the body to produce its own naturally occurring growth factors to promote blood vessel growth into tissue damaged by peripheral arterial obstructive disease (PAOD). They said their finding could offer a new approach to treating the disease, which rivals coronary artery disease in its prevalence and health impact.

The researchers injected into rabbits with a version of PAOD a gene-carrying molecule, called a plasmid, which carried a gene that is the blueprint for a protein known as the "zinc-finger-activating" (ZFP) transcription factor. Transcription factors are proteins that switch on other genes.

In the rabbits, the gene produced ZFP transcription factor that successfully activated a key blood-vessel-growth gene, called VEGF, whose protein product triggers blood vessel growth, found the researchers.

Importantly, the researchers demonstrated that this plasmid stimulated the production of three different forms of VEGF, much as the body would on its own. The researchers said they believe that the latest finding is an important advance in the field of therapeutic angiogenesis -- the process of blood vessel growth -- because past studies of VEGF in humans have only involved one form of VEGF and have seen only limited success..

In addition to stimulating new vessel growth and improving perfusion in the damaged leg tissue, the treatment also appeared to prevent the programmed cell death, known as apoptosis, of muscle cells starved of blood supply but not yet dead, the researchers reported.

The results of the Duke study, led by cardiologist Brian Annex, M.D., are scheduled to be published in the Oct. 19, 2004, issue of the journal Circulation, and are available on-line at http://circ.ahajournals.org/.

"Peripheral arterial obstructive disease, which has a national incidence approaching that of coronary artery disease, is a major health care issue for which there are few effective remedies," Annex said. "This new agent may provide a novel and effective approach to treating a disease that can be just as debilitating as coronary artery disease."

The National Institutes of Health (NIH) has just begun a clinical trial using the plasmid, and Duke will also initiate a similar clinical trial in the coming months.

It is estimated between 8 to 12 million Americans suffer from PAOD. In mild cases, known as intermittent claudication, patients feel muscle pain upon exertion. More severe cases, known as critical limb ischemia, can lead to gangrene or tissue death, often necessitating amputation of the effected limb. While there are drugs and invasive procedures for the disorder, none are particularly effective, the researchers said.

VEGF, because of its ability to stimulate new blood vessel growth, is a naturally occurring substance that has intrigued scientists for years, said the Duke researchers. Cancer specialists, for example, are looking at ways of blocking VEGF-induced blood supply to tumors, while cardiologists are attempting to harness its properties to replenish blood flow to starving tissues throughout the body.

Earlier studies in mice had shown that the ZFP-carrying plasmid could induce VEGF production and stimulate angiogenesis, but the Duke study was the first one to show efficacy in an ischemic model.

"While we've have limited success using VEGF for patients with peripheral arterial disease, we feel that new approach will have a better chance of succeeding," Annex said. "In previous studies, only one form of the VEGF protein was used. This new approach appears to give the body control over the production of the amounts and types of VEGF that it needs."

For their experiments, the researchers induced limb ischemia in the hind legs of rabbits. Ten days later, they injected the plasmid into the effected legs. At regular intervals during the next 32 days, the researchers measured the effects of treatment and found that when compared to the non-treated legs, the treated legs had an increase in capillary density, a positive increase in cellular proliferation and improved tissue perfusion.

Additionally, the researchers found significant increases in the circulating levels of three forms of VEGF VEGF-121, VEGF-165, and VEGF-189.

"Each form varies in its affinity for binding to tissue and may different effects," Annex explained. "VEGF-121, for example, is fairly soluable, so when you inject it into the leg, it travels throughout the body. This is the form used in past human trials.

"VEGF-189, on the other hand, does not easily go into circulation, so it stays where you put it," Annex continued. "VEGF-165 is somewhere in the middle. However, what's most important is that we saw elevated levels of all three, which would indicate that the body was creating those forms in the amounts it needed."

The researchers also found that the treatment appeared to protect damaged cells from undergoing the process of apoptosis.

"The results of these preclinical studies demonstrate for the first time that stimulating innate VEGF gene expression leads to the creation of multiple forms of VEGF that appear to provide therapeutic angiogenesis," Annex said.

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