New gene therapy approach shows promise
Contact: Melanie Fridl Ross, University of Florida
352/690-7051; [email protected]
Embargo: Sunday, May 14, 4:45 pm
University of Florida geneticists have hit on an improved way to deliver a genetic "one-two punch" to cells that could someday help patients with an often-fatal hereditary lung-liver disorder, alpha-1-antitrypsin deficiency.
Unlike classic gene therapy, which solely aims to ferry corrective genes into the body to compensate for those that are malfunctioning, this method also seeks to muzzle destructive genes by removing their ability to command protein production. To do so, researchers package the genetic material in a modified adeno-associated virus, or AAV. which delivers corrective genes to cells, along with an enzyme that acts like a pair of molecular scissors, snipping apart mutant genes before they order the creation of liver-damaging proteins.
The findings were reported this week at the joint meeting of the Pediatric Academic Societies and the American Academy of Pediatrics.
"It's the delivery technique that sets this apart," said Dr. Terry Flotte, an associate professor of pediatrics, molecular genetics and microbiology and co-director of the Powell Gene Therapy Center at UF's College of Medicine. "This solves the problem of devising a vector that can deliver genes to a high percentage of liver cells, which has been the major task at hand. And of course, AAV does all the other things that are required - it is long-lasting and nontoxic."
The genetic disorder, the second most common among Caucasians, causes early emphysema and severe liver disease. It affects an estimated 100,000 Americans. Alpha-1-antitrypsin is produced by the liver and protects the lungs from injury by a common enzyme that normally fights bacteria and cleans up dead tissue. Those affected do not generate enough of the protein to adequately protect the lungs, and permanent and irreversible damage results.
Many people with the disorder also battle liver problems, apparently caused by a defective version of the protein that accumulates in the liver.
"If you look at alpha-1-antitrypsin-deficient individuals when they are born, about 20 percent have some liver problems, and 20 percent of that 20 percent go on to have severe liver problems and die or get transplanted," said Dr. Mark Brantly, a professor of medicine and of molecular genetics and microbiology at UF's College of Medicine. "The caveat is all alpha-1 patients have a lifelong risk of increased liver problems.
"Now we're finding that if you live long enough, as an alpha-1-antitrypsin-deficient individual you'll get liver disease -- you pay now or pay later," he added. "There's a lifelong increased risk of liver cancer as well. So though we tend to think about this sometimes as a problem among children (with alpha-1), it really is a problem of all alpha-1 patients and becomes more of a significant problem over time."
The research team also includes Mark Brantly, a professor of medicine and of molecular genetics and microbiology at UF's College of Medicine; Alfred S. Lewin, a professor of molecular genetics and microbiology in UF's College of Medicine; and graduate student Thomas Conlon. Their studies were funded with the support of the Powell Gene Therapy Center at UF and the National Institutes of Health, and took place in Flotte's laboratory.
Next, UF scientists plan to test the approach in culture in human cells that express the alpha-1-antitrypsin defect. These cells will be obtained through blood samples or lung biopsies.
"We're working hard, but it's going to be awhile before we study this in humans," Brantly said. "We need to make sure we're not causing any kind of toxicity with these procedures. After these early experiments, we're going to be looking at mice that have been given the abnormal alpha-1 gene to see if we can fix it in them."
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