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'Mini-Gene' May Help Cystic Fibrosis Patients

Using shortened version may lead to therapy for debilitating disease

WEDNESDAY, Feb. 20, 2002 (HealthDayNews) -- A shortened version of the gene implicated in cystic fibrosis could, with further refinements, lead to gene therapy to correct the human form of this ultimately fatal lung disease.

The "mini-gene" appears to function just like the full gene in laboratory cultures and in the mouse version of the disease, say researchers at the University of Iowa. Their work appears in yesterday's issue of the Proceedings of the National Academy of Sciences.

An expert in cystic fibrosis research says the findings are intriguing, and they support previous research on these so-called "mini-genes."

Cystic fibrosis (CF) is a genetic disease in which cells lining organs like the lungs and pancreas don't deal with chloride properly, resulting in production of a thick, sticky mucus.

People with the disease, which affects roughly 30,000 Americans, have very salty skin and suffer from chronic coughing, wheezing and pneumonia. They also experience poor weight gain, despite a huge appetite, and bulky stools. CF patients require an enriched diet. Antibiotics treat repeated lung infections, and vigorous pounding on the back and chest can loosen clogged mucus in their lungs.

The gene linked to cystic fibrosis is called CFTR, which normally controls how chloride flows across a cell's membrane. When this gene is mutated, this flow is disrupted, causing CF.

Once scientists had identified and cloned CFTR, it seemed like an ideal target for gene therapy, but the search continued for an ideal method for delivering the gene into the body.

According to lead investigator Lynda S. Ostedgaard, an associate research scientist in internal medicine, one of the most promising delivery systems in CF is the adeno-associated virus (AAV), a small, harmless virus. It has already been used in a clinical trial of gene therapy in people with CF.

However, while nearly all of AAV's genetic information can be removed, it's still not big enough to carry the entire CFTR gene. The team's ultimate goal is to use AAV, but for the purposes of this study, they instead used a larger adenovirus to deliver the therapy.

Ostedgaard and her colleagues removed parts of the CFTR gene from a region known as the R domain. This trimmed CFTR gene was designed to create a similarly short CFTR protein in lung cells.

Next, they introduced the altered CFTR genes to a cultured laboratory model of a three-layered structure of airway cells taken from lungs of patients with CF during lung transplants.

"All the shortened genes that we made actually made proteins just like they were supposed to in the cells," Ostedgaard says. "They transported chloride nearly as well as normal CFTR. Two of them moved as much chloride as normal CFTR did."

Finally, they tested their shortened genes in mice with the equivalent of cystic fibrosis. "We showed that the shortened protein that we put in moved as much chloride as a full-length protein," Ostedgaard says.

"Shortening CFTR is a viable strategy for gene therapy," she says, although this is an early step. The gene must be shortened further to fit into AAV, she says, and more studies in laboratory cultures and animals must be completed.

Christopher Penland, the director of research for the Cystic Fibrosis Foundation, says future studies will need to ensure the therapy produces gene expression in the appropriate cells.

Penland notes there are different "flavors" of AAV, called serotypes.

"In CF, the serotype 5 AAV could be advantageous because it has the ability to bind to airway [linings] and then move into the cells," he explains.

In the meantime, gaining a better understanding of what parts of the gene are critical should guide researchers to new drug studies and help design new medications to treat cystic fibrosis, Ostedgaard says.

What To Do: For more information on cystic fibrosis, visit the National Heart, Lung, and Blood Institute or CF-Web. For details on CF and gene therapy, check out the Cystic Fibrosis Foundation.

SOURCES: Interviews with Lynda S. Ostedgaard, Ph.D., associate research scientist, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa; Christopher Penland, Ph.D., director of research, Cystic Fibrosis Foundation, Bethesda, Md.; Feb. 19, 2002, Proceedings of the National Academy of Sciences
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