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Release: Dec. 1, 1999

UI researchers: step made in developing gene therapy to treat cystic fibrosis

IOWA CITY, Iowa -- A team of University of Iowa Health Care investigators has advanced understanding of how gene therapy might effectively treat the serious lung function loss associated with cystic fibrosis (CF). Some basic problems have thwarted one gene therapy treatment approach which involves using a vector -- a disabled virus or other carrier -- to insert working copies of a specific mutated gene into an affected person's lung cells.

"The UI study addressed two fundamental problems currently preventing progress of gene therapy for cystic fibrosis -- inefficient gene transfer and lack of gene persistence," said Paul McCray, M.D., UI associate professor of pediatrics and co-principal investigator. The team used human cell cultures and in vivo, or animal, models to demonstrate both efficient and lasting gene transfer into airway cells.

The investigators demonstrated functional gene activity that lasted six months in the human cells in culture and six weeks in the rabbits' airways. The findings were published online Nov. 24 by the Journal of Clinical Investigation (available at: ). The print version will be published Dec. 6.

"This is another incremental step toward figuring out how we might apply gene therapy to treat cystic fibrosis," McCray said. "Our findings could lead to new approaches for future CF gene therapy trials."

People with CF have serious lung and digestive problems due to malfunctioning ion channels that normally regulate salt and water secretions to protect the lungs. A specialized protein called the CF transmembrane conductance regulator (CFTR) makes the channel. However, in people with CF, the gene that codes for the CFTR protein is mutated.

Previous research, including a 1998 study McCray led using human cell cultures, demonstrated that a vector, which carries a working copy of the mutated gene, can more effectively enter a cell if it is mixed with a calcium chelator. The chelator binds with calcium to disrupt tight junctions between the cells. The vector can then reach cell receptors and transduce the cell -- cross its surface and deposit the gene.

In the most recent study, McCray's team used a new vector from the retrovirus family, feline immunodeficiency virus (FIV), which causes leukemia in cats but causes no disease in humans. Chiron Technologies in San Diego created the FIV-based retrovirus.

"We saw in both human cell cultures and in rabbits that FIV vectors will transduce, or infect, nondividing cells, which eliminates the need to stimulate cell division to get the vector to work," McCray said. "This is very important because normally very few lung cells are dividing."

McCray said the method of using a calcium chelator-enhanced vector to bolster a vector's ability to transduce cells could be used in a human trial to increase gene transfer efficiency.

"The principle applies to three classes of vectors that investigators use to study gene transfer for cystic fibrosis -- retrovirus, adenovirus and adeno-associated viruses," he said.

The UI study was also significant in its findings on gene persistence, McCray added. The researchers found that the gene transferred by the FIV vector into human airway cells in culture continued to show functional CFTR activity for up to six months. In contrast, the effectiveness of an adenovirus vector wore off after about three weeks. FIV-transduced gene expression in the airway cells of live rabbits lasted six weeks (the duration of the study).

"We think the CFTR gene persists because the FIV vector allows it into the chromosomes of lung cells with the potential to divide and pass the gene on to their daughter cells," McCray said. "Unlike nonviral carriers or an adenovirus, a retrovirus such as FIV has this ability."

In addition to McCray, UI investigators included Beverly Davidson, Ph.D., associate professor of internal medicine and director of the Gene Transfer Vector Core; Guoshun Wang, Ph.D., research scientist in pediatrics; and Joseph Zabner, M.D., assistant professor of internal medicine.

The UI study was funded by grants from the Cystic Fibrosis Foundation, the National Institutes of Health, and the Children's Miracle Network telethon. McCray also received a Career Investigator Award from the American Lung Association. Davidson and Zabner are Fellows of the Roy J. Carver Charitable Trust.

Cystic fibrosis is the most common fatal hereditary disease in the United States. According to the Cystic Fibrosis Foundation, CF affects approximately 30,000 children and adults in the United States. The disease occurs in approximately one of every 3,300 live births and is usually diagnosed in early childhood. Lung function loss due to chronic infection is the most common cause of the shortened life expectancy of people with CF.

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