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Gene Therapy Generates New Blood Vessels

Date:
November 12, 1997
Source:
American Heart Association
Summary:
Through gene therapy, researchers have grown new blood vessels for humans, according to a report presented Nov. 9 at the American Heart Association's Scientific Sessions.

ORLANDO, Nov. 9 --Through gene therapy, researchers have grown new blood vessels for humans, according to a report presented today at the American Heart Association's Scientific Sessions.

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This new therapy, called therapeutic angiogenesis, was successfully used to grow vessels to bypass obstructions of blood flow in the legs of eight people.

The blood circulation in the individuals' legs had become obstructed by atherosclerosis, the same disease process that creates the fat-filled plaques that clog coronary arteries, the blood vessels feeding the heart.

In the experimental therapy, the gene or DNA that produces the growth factor that stimulates the creation of blood vessel cells during the development of the human embryo, is injected into muscles in the patient's legs. The injected DNA "instructs" existing blood vessel cells to regenerate new blood vessels.

Jeffrey Isner M.D., whose team presented the research, conducted at St. Elizabeth's Medical Center in Boston, says the therapy soon will be evaluated in people whose coronary arteries are obstructed by atherosclerosis, putting them at risk for heart attack and death.

"Since this gene therapy approach works in the leg, it should work in the heart," says Isner, who described his first patient in which gene therapy produced new blood vessels in a paper published in August 1996 in the journal Lancet.

If gene therapy proves safe and effective in generating new blood vessels to create a natural bypass around blocked coronary arteries, cardiologists will be able to help patients for whom balloon angioplasty, bypass surgery, drugs and other treatments designed to restore blood flow are unsuccessful or represent a high risk.

Whether this gene therapy will emerge as a primary treatment -- in conjunction with angioplasty, for example, or instead of bypass surgery -- is unknown and depends on future research, says Isner, professor of medicine and pathology at Tufts University School of Medicine and chief of cardiovascular research at St. Elizabeth's Medical Center.

But for now, the gene therapy is helping people with severe atherosclerosis in their legs to avoid amputation. "For the people enrolled in the study, every therapy had been tried and failed," explains Isner. For individuals with critical limb ischemia, which is severe atherosclerosis in the blood vessels in the legs, amputation is often the only way to deal with deadly gangrene of the afflicted limbs.

The study, which began one year ago, did not randomize the patients -- that is, assign them either to gene therapy or conventional therapy. Isner explains that randomization did not occur because for people with such severe disease there is no conventional therapy.

Affecting 100,000 to 200,000 people in the United States, critical limb ischemia is the "most under-diagnosed entity in cardiovascular disease," says Isner. "It often is chalked up to old age, but can be a sign that there is something wrong with the vascular system." Many of his patients have atherosclerosis in their coronary arteries, carotid arteries (blood vessels to the brain that if blocked can cause a stroke) in addition to peripheral vessels in the limbs.

The effectiveness of the gene therapy was gauged by before and after clinical assessments which included diagnostic angiogram, which produces an image that shows blood flow in vessels; magnetic resonance angiography; measurement of the ankle-brachial pressure, and, if possible, exercise testing.

In eight of the 10 treated legs, improved blood flow was demonstrated by magnetic resonance imaging. Angiograms showed evidence of newly visible vessels in seven of the 10 treated limbs.

At follow-up examinations, one to six months after the last injection, blood pressure in the individuals' ankles had increased from 0.33 to 0.47 ankle index. "The blood pressure in the ankle and the arm should be equal," explains Isner.

"At the beginning of the study, the patients' ankle blood pressure was about one-third of the arm's pressure. The 14-point increase fulfills criteria ordinarily used to indicate success after surgery or angioplasty. To my knowledge, this kind of improvement has never been shown to occur without surgery or angioplasty in this group of patients. This kind of improvement does not occur spontaneously," he points out.

Individuals were also asked to gauge the amount of resting pain (pain in the legs while resting) before and after the therapy. Individuals with severe atherosclerosis in their legs typically suffer a lot of resting pain that interrupts their sleep. Like angina, or chest pain, it is caused by impaired blood flow. Six patients reported experiencing less "rest pain." In four of the seven legs with skin ulcers resulting from reduced blood flow, healing or marked improvement occurred.

The amount of time spent in walking a certain distance improved in all five individuals tested.

Only one of the study participants had to undergo limb amputation. When the 39-year-old woman joined the study, she had severe atherosclerosis in both legs. "The front half of one foot was already black due to the onset of gangrene," Isner says. In the woman's other leg, gangrene had begun in her toe. Gene therapy was applied to both legs and halted the gangrene in the least afflicted leg but failed in the other leg "because it was too far gone," says Isner.

"When she came to us, she was facing two lower limb amputations," he adds. "Without this therapy, she would have been a double amputee." The leg that was amputated was the only one of the two limbs in the study that deteriorated. Another woman in the study also avoided amputation as a result of the gene therapy, he notes. For one patient, there was no improvement.

Other researchers previously found the growth factor produced by the gene therapy was released by human tumor cells. "To grow, tumors need a blood supply," explains Isner, "so tumor cells secrete vascular endothelial growth factor to generate new blood vessels. The factor also is produced in the developing embryo."

The gene for this growth factor, which was derived from a human pituitary tumor, is being replicated in Isner's laboratory at St. Elizabeth's Medical Center, which funded the clinical trials of the nine patients.

For the injections, the gene was not attached to a virus or another "Trojan horse" medium to transport the DNA inside the cell. The "naked" DNA was administered twice, four weeks apart.

Co-authors are Iris Baumgartner, Ann Pieczek, Richard Blain, Orit Manor and Kenneth Walsh.


Story Source:

The above story is based on materials provided by American Heart Association. Note: Materials may be edited for content and length.


Cite This Page:

American Heart Association. "Gene Therapy Generates New Blood Vessels." ScienceDaily. ScienceDaily, 12 November 1997. <www.sciencedaily.com/releases/1997/11/971112070603.htm>.
American Heart Association. (1997, November 12). Gene Therapy Generates New Blood Vessels. ScienceDaily. Retrieved November 28, 2014 from www.sciencedaily.com/releases/1997/11/971112070603.htm
American Heart Association. "Gene Therapy Generates New Blood Vessels." ScienceDaily. www.sciencedaily.com/releases/1997/11/971112070603.htm (accessed November 28, 2014).

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