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Bridging Genetic Gap in Cystic Fibrosis

Gene fix in lab raises hope for future gene therapies, says expert

FRIDAY, Dec. 28, 2001 (HealthDayNews) -- Throwing a genetic bridge across a potholed cellular transport system may balance the way salt is used in the lungs of cystic fibrosis (CF) sufferers, allowing bacteria to be cleared normally and preventing infection, says new research.

In a laboratory experiment, scientists at the University of Iowa fixed a flawed protein that normally carries chloride ions through cells. This is the most common genetic defect for people with CF, and the technique someday could translate to a new treatment for this disease that kills people at an average age of 30, say the researchers. Shuttling the ions through the cells balances their fluids and electrolytes and prevents infections by clearing bacteria from cell surfaces.

CF is a genetic disease affecting roughly 30,000 Americans. If each parent carries a CF gene, a child will have a one-in-four chance of getting the disease; a child who inherits only one defective gene won't show the disease. About one in 23 people in America carry at least one defective gene, says the nonprofit group Cystic Fibrosis Research. Because of the abnormal salt transport mechanisms in their cells, people with CF produce thick, sticky mucus around their lungs and other organs.

CF patients have salty-tasting skin and experience persistent coughing, pneumonia and poor weight gain. CF has no known cure, and patients rely on antibiotics, inhalers and chest-pounding therapy to keep the mucus from clogging their lungs.

For the lab experiment, the scientists used a cell model from airways that resemble the airways of CF patients, says a report in the January 2002 issue of Nature Biotechnology.

Using a technique called spliceosome-mediated RNA trans-splicing, (SMaRT), lead investigator John Engelhardt and his colleagues used a crippled cold virus to deliver a pre-therapeutic molecule (PTM) -- the missing genetic information -- to the defective protein.

Treatment must force both the expression of a normal copy of the gene and correct the defective gene. "Having a little bit of a mutant protein can sabotage the whole system," says Engelhardt.

The PTM corrected defects in RNA, or ribonucleic acid, a chemical that delivers DNA instructions to the section of cells where proteins are made. The technique restored 16 percent of normal transport protein levels, the researchers say.

"The advantage of correcting genetic defects at the RNA level is that you will only express the corrected protein product in the cells that already express the gene that you're targeting," says Engelhardt. "If you're using the DNA vector with current technologies, it goes into just about every cell."

In an accompanying commentary, Dr. Ronald Crystal says that while several technological hurdles remain before the technique could become a clinical reality, it offers hope of a treatment for CF.

"You have a bunch of building blocks, one of which is bad. The idea is to trick the cell into using your building blocks instead of its own building blocks," says Crystal.

He says it will be several years before the efficiency of the technique is improved to insure that mistakes don't happen. "You've got to make sure that the correct sequences go in the correct place," he says.

Engelhardt says clinical trials of the PTM therapy are at least five years away and that therapies based on the technology could be even farther away.

Still, Engelhardt says the potential for this technique extends beyond this disease. "There are probably even better applications for this technology than CF," such as certain blistering skin diseases where a dominant genetic mutation sabotages normal cell function, he says.

What To Do

Check this primer on genomics from the Department of Energy Human Genome Program.

You can also find out more about CF from the Cystic Fibrosis Foundation or the National Heart, Lung, and Blood Institute.

SOURCES: Interviews with John F. Engelhardt, Ph.D., professor, department of anatomy and cell biology, director, Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases, University of Iowa, Iowa City; Ronald G. Crystal, M.D., professor of medicine, chief, department of pulmonary and critical care medicine, director, Institute of Genetic Medicine, Weill Medical College, Cornell University, New York, N.Y.; January 2002, Nature Biotechnology
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