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UI researchers find potential gene therapy for cystic fibrosis

IOWA CITY, Iowa --A team of University of Iowa investigators may have found a way to permanently deliver therapeutic genes to the lungs of patients with cystic fibrosis (CF), the most common fatal hereditary disease in the United States.

The research using human cells in laboratory cultures indicates that the method could be used to permanently cure CF and other genetic lung diseases, said Dr. Paul McCray, associate professor of pediatrics in the UI College of Medicine and co-principal investigator.

The findings were published in the December issue of the Journal of Virology. The other co-principal investigators of the study were Beverly L. Davidson, Ph.D., UI associate professor of internal medicine and director of the Gene Transfer Vector Core, and Guoshun Wang, Ph.D., UI research investigator in pediatrics.

According to the Cystic Fibrosis Foundation, CF affects approximately 30,000 children and young adults in North America. The disease occurs in approximately one of every 3,300 live births and is usually diagnosed in early childhood. Reduced lung function, lung infection and liver and pancreatic disease are among the serious conditions that can reduce the life expectancy of a person with CF. The median age of survival for a person with the disease is 31 years.

CF is caused by the malfunction of an ion channel that regulates secretion of salt and water that protect the lungs. A specialized protein, known as the CF transmembrane conductance regulator (CFTR), makes the channel. The gene that codes for the CFTR protein is mutated in people with CF.

McCray said the UI research project was designed to complement other CF treatments under laboratory investigation, including another UI study. Those methods involve inserting the CFTR gene into a vector-a nonviral carrier or an adenovirus-to facilitate transferring the gene into cells lining the airway.

In some cases, the mucous produced by the diseased lungs may trap the vector and prevent it from depositing the CFTR gene in the cells. With chemical assistance, the vector successfully inserts the gene into the cells and CFTR is produced. While the results are beneficial, the effect is not lasting because the gene itself is not reproduced as the cells divide. Because CF is a chronic, progressive disease, the CFTR gene would have to be reintroduced to maintain production of the protein that protects the ion channel.

In the study led by McCray and researchers at the UI and Chiron Laboratories in San Diego, the team found that a retrovirus "might be used on a one-time basis and offer a permanent cure for patients with cystic fibrosis," McCray said.

A retrovirus, unlike a nonviral carrier or an adenovirus, can integrate into the host DNA.

"A retrovirus has the advantage of permanently placing its gene into the host cell," McCray said. "So when the cells divide, they are able to reproduce the gene."

In the case of CF, the gene would then code for the needed protein, CFTR, on an ongoing basis, allowing the ion channel to function properly.

At the same time, the team found that there are limitations that prevent the easy introduction of the retrovirus, known as murine leukemia virus (MuLV), into the airway cells. The investigators discovered that the retrovirus cannot easily cross the apical, or top, surface of the cells.

Searching for a way to overcome that difficulty, the team found that the retrovirus readily enters cells from the basolateral, or bottom, side of the cells. The study results suggest that the bottom surface of the cells has receptors that accept the retrovirus.

In addition, the team studied whether disrupting the tight junctions between the cells would make it easier for the retrovirus applied to the apical surface to enter and deliver the CTRF gene. The junctions require calcium, which can be removed through treatment with EGTA, a chemical that binds with calcium.

"Removing the calcium from around the cells opens the tight junctions, which act as a sort of cement between the cells," McCray said. "When the junctions open, the retrovirus can reach the receptors."

The researchers will continue their studies of the MuLV-based retrovirus gene transfer. "Our next step is to develop methods to apply this approach to an animal model," McCray said. "Our early experiments look encouraging."

In a previous cystic fibrosis-related study at the UI, a team of investigators, including Dr. Michael Welsh, professor of internal medicine and Howard Hughes Medical Institute investigator, studied the use of an adenovirus in ferrying the CFTR gene into airway cells.

Welsh and his colleagues found that an adenovirus coupled with a calcium phosphate complex can more easily enter human airway epithelial cells in culture than when the virus alone is used. The team found that the gene is then transferred to a sufficient number of cells to ultimately correct the ion channel deficit. The findings of that study were published in July in the Journal of Clinical Investigation.