Hope for heart patients may be gene therapy away

In a follow-up study of patients with severe coronary artery disease who were given angiogenic gene therapy a decade ago in an attempt to rebuild damaged blood vessels, researchers observe that the patients showed improved survival rates and quality of life

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NEW YORK—In a follow-up study of patients with severecoronary artery disease who were given angiogenic gene therapy a decade ago inan attempt to rebuild damaged blood vessels, doctors at Weill Cornell MedicalCollege, Baylor College of Medicine and Stony Brook University Medical Centerobserved that the patients showed improved survival rates and quality of life,according to an article recently published in the journal Human Gene Therapy.
From 1997 to 1999, 31 patients with severe coronary arterydisease—who had blockages in not just one, but several coronary arteries, aswell as in their small capillaries—were given a direct injection into theirheart muscle of gene therapy called adenovirus encoding angiogenic growthfactor, or AdVEGF121. These patients had already had coronary bypass surgery orstents placed in their chests, and had no other medical intervention availableto them, notes Ronald G. Crystal, chairman and professor of Genetic Medicine atWeill Cornell.
"The people who entered this trial had chest pain when theywould just walk across the room," Crystal tells ddn. "We came up with a concept that we likened to a big highwaythat goes around the city. If there is an accident on the road, you bypass itby taking another route. We wanted to create detours around the arteryblockages the patients had, taking the heart back to what it was when they werean embryo."
The gene used in the study is the same gene the heart usesto make coronary arteries when a patient is am embryo, says Crystal.
"It is also the primary gene used by the heart to make itsown blood vessels," he says.
In the study, patients were divided into two groups. Group Areceived both conventional coronary artery bypass grafting and gene therapy,while group B received only gene therapy. There was no control group. 

Reviewing the medical records of these patients andfollowing up with them nearly a decade later, the doctors observed that thegene therapy helped rebuild weak and damaged blood vessels in these patients.For Group A, the survival rate was 40 percent, and in Group B, was 31 percentat the 10-year follow-up mark. Of the 18 patients who died, causes of deathranged from cancer to cardiac related issues.
"In addition, we observed no adverse effects or safetyissues," says Crystal.
The current study represents the longest documentedfollow-up of a cohort of individuals having been administered a gene transfervector in vivo. However, Crystal underscoresthe fact that because the original trial had no control group, there arecaveats to the doctors' interpretation of the results.
"We were only able to compare the results to literatureinvolving equivalent subjects," he says. Writing in the article, he adds:"Although interpretation of these data is limited by our lack of moreformalized trial design over this prolonged interval, they nevertheless suggestthe long-term safety of this intervention, even in patients with late-stage,diffuse critical coronary artery disease. Future placebo-controlled clinicaltrials that include a rigorous focus on long-term event-free survival ratesand/or sustained reduction of symptoms and health-related quality of lifeappear warranted to substantiate these preliminary findings regarding safety,as well as to evaluate the differential treatment efficacy of gene therapies."
Crystal and his colleagues are initiating a new, prospectiveplacebo-controlled randomized trial of direct adenovirus-mediated angiogenicgene therapy in an attempt to definitively address this issue.
"This trial will probably involve a total of 35 patients andtake about 18 months. We hope to be finished by 2015," says Crystal.
For the researchers at the three universities, their majorfocus will continue to be on gene therapy, "which is essentially a drugdelivery strategy where doctors use a gene instead of a conventional drug,"explains Crystal.
"I think gene therapy is experiencing a real resurgenceright now," he says. "Several applications for gene therapies have shown to beefficacious in conditions like immunodeficiency diseases and leukemia. I thinkover the next five years or so, we'll see several approvals. We have had manydiscussions with the FDA, and they are very engaged and positive about thepotential for gene therapies."

The article, "Long-Term Follow-up Assessment of a Phase 1Trial of Angiogenic Gene Therapy Using Direct Intramyocardial Administration ofan Adenoviral Vector Expressing the VEGF121 cDNA for the Treatment of DiffuseCoronary Artery Disease," ran in HumanGene Therapy's online edition on Nov. 8. The authors acknowledged financialsupport from the Lisa and James Cohen Foundation, the Qatar Foundation,Weill-Cornell Medical College in Qatar and the U.S. National Institutes ofHealth.

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