Biomedical researchers have corrected the crucial defect that cripples the lung cells of cystic fibrosis patients, raising the possibility that gene therapy can be developed to treat those who suffer from the common childhood killer.
Just a year after researchers found the defective gene that causes cystic fibrosis, scientists have inserted normal copies of the gene into cells and shown that, at least in the laboratory, the new genes reverse the chief symptom of the inherited disease.
The cells of cystic fibrosis patients produce an abnormally sticky mucus that fills the lungs and makes victims far more vulnerable to the infections, inflammations and lung scarring that kill half of all sufferers by their twenties.
The research, which is to be reported by two groups in two scientific journals, Cell today and Nature next week, demonstrates the speed at which genetic studies are moving forward and raises the possibility that cystic fibrosis (CF), the most common inherited fatal disease of children and young adults in the United States, may soon be treated with a revolutionary procedure called gene therapy.
"Only a few years ago the idea of introducing normal genes into the CF lung to correct its fatal susceptibility to infection was science fiction," said Paul Quinton of the University of California at Riverside. "Now the accomplishments of these investigators seem to press the fiction inspiringly close to reality."
"This is a major hurdle," said Robert Beall, vice president and medical director of the Cystic Fibrosis Foundation, which supported in part the research. "This is clearly going to move cystic fibrosis up the list as a candidate for gene therapy."
"It is a very nice advance, a big advance," said Ronald Crystal, chief of the pulmonary branch of the National Heart, Lung and Blood Institute, who is working on gene therapy for cystic fibrosis. "It demonstrates that the normal gene can reverse abnormalities caused by the defective gene."
The work comes at a time when researchers have been electrified by the possibility that human disease can be treated and perhaps even cured by inserting copies of normal genes into the body to take over functions that defective genes are failing to carry out.
The first attempt at gene therapy was performed last week at the National Institutes of Health, when researchers gave a 4-year-old girl with a rare inherited immune dysfunction about one billion genetically altered blood cells that had been removed from her two weeks earlier. Results of the experiment will not be known for months.
In the study on cystic fibrosis, two teams of researchers used specially engineered viruses to insert copies of normal CF genes into cells taken from the pancreas and lungs of patients with the disease.
Viruses are used because they naturally splice their genes into the chromosomes of cells they infect. The viruses in this case were given the CF gene to include in the splicing process. Other virus genes needed to reproduce the virus were deleted.
In a cell with normal genes, chloride ions and water move into and out of the cell. But with cystic fibrosis, the pumps and channels are blocked. Chloride ions enter the cell but cannot be pumped out and, as a result, the phenomenon of osmosis causes water to diffuse into the cell from the mucus that coats its outer surface. The dehydrated mucus turns thick and sticky. In the lung's airway, this mucus becomes infected with bacteria and other microorganisms, inflamed and over time the tissue becomes scarred and damaged.
The researchers, however, found that the insertion of a normal gene allowed the cells in the laboratory to regain normal function and resume the proper balance of water and chloride ions.
The work was performed by two groups. Alan Smith of Genzyme Corporation, Douglas Jefferson of Tufts University and Michael Welsh of the Howard Hughes Medical Institute and the University of Iowa and colleagues are to publish their report in the Sept. 27 issue of Nature. James Wilson and Francis Collins of the University of Michigan and the Howard Hughes Medical Institute, and Ray Frizzell of the University of Alabama report their study in today's issue of Cell.
Scientists now hope to devise a way to insert normal genes into the cells of patients without having to remove the cells from the patient's body, as was done with the 4-year-old girl. Since the most affected cells line the lung's air passages, the researchers believe that an aerosol carrying the genetically engineered viruses can be inhaled by patients.
It is also possible that instead of the gene, the protein it produces can be delivered to the lungs, where it could be absorbed by the cells.
However, researchers cautioned that they are still unsure how effective introducing genes or proteins would be. For example, will the therapy work if only half the cells in the airways harbored normal genes?
Also, the scientists said, even if it worked, the therapy would still be far from a cure. Since the affected cells are continuously being sloughed off and replaced, a patient would have to keep inhaling new genes every day or so. Researchers do not know where the "stem cells" lie that give birth to the cells that line the air passages of the lungs. If they discovered the location of these mother cells, they could theoretically target them for infection with normal genes, which would then be passed on to all the daughter cells.
The next step is the development of an animal that could serve as a surrogate for experimentation. At least five research groups are trying to create mice with the genetic defect that leads to cystic fibrosis. Officials at the Cystic Fibrosis Foundation believe such an animal model will be introduced within a year.