Dec. 13, 2000 GAINESVILLE, Fla.---Turning the promise of gene therapy into reality has been more difficult than scientists once hoped, but University of Florida researchers have identified a strategy for overcoming one barrier to successfully treating the lung disease cystic fibrosis.
Patients with CF produce thick mucus that clogs airways, predisposing them to chronic lung infections. Scientists at the UF Genetics Institute and the department of pediatrics have discovered these same secretions prevent lung cells from taking up much of the corrective DNA inserted during gene therapy.
Now UF researchers have found one potential solution: an anti-inflammatory protein naturally produced by the body. In laboratory experiments conducted in cell cultures, the scientists found that if they added alpha-1-antitrypsin to the lung fluids from CF patients, the number of cells integrating the new DNA tripled.
"At scientific meetings, many people have been talking about how a major problem in gene therapy trials is that relatively few cells begin expressing the new genes," said Dr. Isabel Virella-Lowell a pediatric pulmonary fellow at the UF College of Medicine. "We have encountered the same issue in our early clinical trials in cystic fibrosis. That's why it's significant that at least in cell cultures, we can use alpha-1-antitrypsin to reverse the limiting effects of the mucus."
Virella-Lowell's article describing the research was published in October in the journal Gene Therapy. The research team was headed by Dr. Terence R. Flotte, director of the Powell Gene Therapy Center and interim director of the UF Genetics Institute, and included Dr. Mark Brantly, a professor of medicine, and molecular genetics and microbiology; and researchers Amy Poirier and Kye A. Chesnut.
Cystic fibrosis has been an early target for gene therapy researchers because the disease is caused by a single faulty gene. In CF, this gene upsets the normal passage of salt and water through the body's cells. Among the most severe consequences is the excessive mucus in the lower airways of the lungs - often leading to permanent lung damage. An estimated 30,000 Americans have the disease; most patients die before they reach 30.
When the gene was first identified in 1989, the discovery was greeted with great optimism that a cure would soon follow. But it has proved to be a formidable task to find the right mechanism to deliver the DNA, coax cells to incorporate the corrective gene and activate it so it begins functioning.
In their early clinical trials at Shands at UF medical center, scientists have found no adverse effects in patients who received corrective genes. The DNA was packaged inside adeno-associated virus - also known as AAV - an apparently harmless virus that dwells problem-free in most people.
In continuing clinical studies, the scientists are trying to find the proper dosage for treating the disease, a job that will be made easier if they can encourage a higher percentage of cells to take up the inserted genes.
That's where the most recent laboratory research fits in.
The scientists compared lung fluid samples collected from CF patients with those from other people who do not have the disease. The researchers were looking to see whether these fluids would block the integration of new DNA into bronchial cells.
When they found that the CF fluids did, the researchers went on to show that alpha-1-antitrypsin effectively neutralized this effect. When added to CF lung cell samples, the protein more than tripled the number of cells acting upon the new genes - from about 15 percent of the cells to about half.
The findings are likely to guide future clinical trials, with UF scientists testing the effectiveness of administering alpha-1-antitrypsin in conjunction with gene therapy for cystic fibrosis. This work has been funded by the National Institutes of Health and the Cystic Fibrosis Foundation.
"The drive to find a cure for CF is like running a steeplechase," said Flotte, "only in this case, we won't know if we've finished the race until after we've cleared the last hurdle. What we do know is that this particular barrier to gene therapy is reversible, and so we haven't been knocked off the track yet."
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