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UI cystic fibrosis researchers find a new way to look at an old problem

IOWA CITY, Iowa -- Replacing a mutated gene with a normal one seems to be a simple and straightforward way to cure a genetic disease. However, the process is anything but simple, according to Michael Welsh, M.D., University of Iowa professor of internal medicine and Howard Hughes Medical Institute investigator.

Welsh has found a way to make gene transfer into the cells that line the bronchial passages a little easier ­ a method that may pave the way for a cure to cystic fibrosis. His findings were published in the July issue of Journal of Clinical Investigation.

Cystic fibrosis (CF), the most common lethal hereditary disease in the United States, is caused by the malfunction of an ion channel that is critical for maintaining the secretions of salt and water that protect the lungs. The cystic fibrosis transmembrane conductance regulator (CFTR) protein makes the channel, and the gene that codes for the CFTR protein is mutated in people who have CF. A normal gene inserted into affected airway cells allows production of working ion channels, and scientists have pursued gene therapy as a way to fix those ion channels and cure CF. Viruses enter cells easily, and researchers initially believed that attaching the CFTR gene to a virus would guarantee its transfer into a cell where it could do its work. They thought that an adenovirus, the virus responsible for the common cold, would be an especially good ferry, or vector, to carry the CFTR gene into the cells lining the airway. They were wrong.

"As it turns out, the adenovirus is not very efficient in getting into the airway epithelial cells," Welsh said. "There aren't many receptors on the outer membrane of the cells, and only a few viruses get through. Which is good, because just breathing brings those cells in contact with the outside environment, and the bronchial lining cells provide a tough barrier that protects the airway."

It's good for the body, not so good for gene therapy. Normally, when a virus gets through the cell membrane it rapidly replicates and infects other cells. That is how an infection readily develops even when only a few viruses make it through the cell barrier. When used as a vector, however, the virus is altered so that it cannot replicate when in a cell. If only a few viruses make it through the epithelial cell barrier, only a small percentage of genes are transferred into airway cells, not enough to correct the ion channel deficit.

Welsh and his colleagues noted that a solution of calcium and phosphate, simple salts, forms a precipitate that attaches to the adenovirus. They also noted that the adenovirus calcium phosphate complex (Ad:CaPi) carried the gene into human airway epithelial cells in culture more efficiently than the virus alone. When investigators administered the gene/Ad:CaPi complex into the lungs of mice, they found that the gene was transferred to a significant number of airway cells. Enough, Welsh predicted, to correct the ion channel deficit.

"We don't know exactly how the Ad:CaPi complex works to transfer the gene," Welsh said. "We do know that it helps the complex attach to the cell, then it is inserted into the membrane, then taken into the cell." What the scientists do know is that if the Ad:CaPi complex transfers the CFTR gene into human lungs as well as it does into human cells in culture and mice lungs, that they are getting closer to their goal of developing methods that can be used in people.

However, Welsh is not ready to test the Ad:CaPi complex in people.

"We want to find out more about how it works, test it in other animals to learn more about its safety before trying it in humans," he said.