Gene, biochemical fixes sought for CF.

When it comes to cystic fibrosis (CF), three seems to the magic number. Just three years ago, scientists pinpointed the faulty protein that caused people with the disease to produce thick mucous and sustain the lung and other organ damage that leads to an early death. Now, researchers report progress in three very different approaches to compensate for or correct this protain defect. In one, they demonstrated the feasibility of gene therapy as a treatment option in three CF patients.

Because of a genetic defect, people with cystic fibrosis lack functional copies of a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), which works like a channel to control the flow of chloride ions in and out of cells. Thus cells produce a 'dehydrated" mucous, says Michael J. Welsh, a Howard Hughes Medical Institute researcher at the University of Iowa in Iowa City. His team now reportse that cells lining the noses of people with this disease do take up and use a transferred gene that makes normal copies of CFTR.

A second anti-cystic fibrosis approach calls for using one of the body's own chemicals to get another protein channel to make up for the nonfunctional CFTR protein, while the third would make better use of the defective CFTR protein.

Several research teams are developing gene therapies to compensate for the defective CFTR (SN: 12/12/92, p.405). Some, like Welsh's group, put copies of the gene responsible for the normal CFTR protein into genetically modified adenoviruses, which typically cause colds. The virus transfers the gene when it infects a cell.

Applying even small amounts of modified virus to the nasal lining of three CF patients restored the voltage indicative of normal chloride-ion movement, Welsh reported last week in Dallas at the North American Cystic Fibrosis Conference and in the Oct. 22 CELL. At that meeting, Ronald G. Crystal of the National Heart, Lung, and Blood Institute in Bethesda, Md., said he saw simnilar changes in four of his patients who underwent gene therapy.

Before researchers can demonstrate that this approach may actually treat cystic fibrosis, they must first increase the amount of genetic material transferred, transfer functional genes to the lining of the lungs, and ensure they have a safe and effective way to transfer the genes, Welsh cautions. Some researchers worry that the effective dose of adenovirus will pose safety risks, but these early results suggest otherwise, Crystal adds.

Taking a different tack, Richard C. Boucher of the University of North Carolina at Chapel Hill and his group have shown that in mice bred to develop symptoms of cystic fibrosis, the severity of disease varies from organ to organ depending on the amount of another channel protein produced by cells in these organs. Pilot studies indicate that a substance called uridine 5[feet] -triphosphate (UTP) can help people with cystic fibrosis clear the thick mucous from their airways, Boucher'> group reported eat the Dallas meeting. UTP increased fluid flow by making an alternative channel active enough to make up for what CFTR fails to do, report Sheldon S. Miller at the University of California, Berkeley, and his colleagues in the Oct. 15 SCIENCE.

In many people with cystic fibrosis, the faulty gene results in the loss of one of the amino-acid building blocks that make up CFTR. And this causes newly made copies of CFTR to stick permanently to a protein that helps fold it into the right shape, reports Yiping Yang, a molecular biologist now at the University of Pennsylvania Medical Center in Philadelphia.

Whilee at the University of Michigan Medical School in Ann Arbor, Yand and his colleagues observede that normal and defective versions of CFTR both form in a cellular compartment called the endoplasmic reticulum. The versions attach to a "chaperone" protein called hsp70 for folding. But the defective protein never lets go and therefore never leaves its birthplace to start working as a channel, they report in the Oct. 15 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES. This defective version would work right if it could only get to the cell membrane, says Yang. So treatments that split hsp 70 from CFTR should restore CFTR's ability to function, he theorizes.