MEDICINE / CYSTIC FIBROSIS : Genetic Breakthrough With Mice Hailed by Experts as ‘Major Victory’

Researchers have produced mice that develop cystic fibrosis, a feat that some experts term a “major victory” in the quest to overcome the disabling disease.

Development of the mouse “model” of the disease, reported by North Carolina scientists today in the journal Science, should provide researchers with an invaluable tool in the search for new therapies for the disease, which usually is fatal by age 40.

“This is a dream come true for CF researchers,” said Dr. Richard C. Boucher, a professor of medicine at the University of North Carolina at Chapel Hill School of Medicine and a member of the team that developed the mice. “We now have an animal model in which we can test new therapies for cystic fibrosis in a fast, thorough and safe manner.”

Using genetic engineering techniques, the researchers inserted a version of the faulty gene that causes the disorder into mouse embryos. When the adults grown from the embryos mated, some of their offspring developed the symptoms of cystic fibrosis. Cystic fibrosis is the most common fatal genetic defect in the United States, affecting an estimated 30,000 people. The faulty gene that causes the disorder was discovered only three years ago.

“It should significantly speed our progress toward the ultimate cure” for the disease, said Robert K. Dresing, president of the Cystic Fibrosis Foundation.

“It’s a pretty stunning development,” said molecular geneticist Francis Collins of the University of Michigan, one of the discoverers of the cystic fibrosis gene.

Researchers have been in a frantic race to produce the CF mice ever since the gene was identified. At least five other groups have also been attempting to produce the animal model, and one of those is expected to report similar results shortly.

Even though the technology for producing such “knockout” mice--in which a key gene has been knocked out or replaced--is well known and widely available, the CF gene has proved particularly difficult to work with for reasons that are not yet clear. So molecular biologist Beverly Koller and pathologist Oliver Smithies were jubilant when they produced the mice in their laboratories.

One in every 20 Americans, more than 12 million people, carry a copy of the defective gene that causes cystic fibrosis. The disorder occurs in approximately one in every 2,000 live births, with about 1,400 new cases diagnosed each year.

It causes the production of an abnormally thick, sticky mucus which clogs the lungs and leads to life-threatening infections and lung damage. Similar mucus elsewhere obstructs parts of the pancreas, preventing enzymes necessary for digesting food from reaching the intestines.

Early in this century, the infections and blockage typically killed patients in their teens. Therapy has more than doubled the expected life span of cystic fibrosis patients, but does nothing to affect the underlying disease.

No sooner had Collins and his colleagues identified the CF gene, called CFTR, than researchers began attempting to develop a knockout mouse with it. To do so, they took a strand of genetic material containing the defective CFTR gene and mixed it with certain cells from a mouse embryo. In about one in every 300 of the cells, the defective gene replaced the normal CFTR gene.

The researchers then placed the altered cells in embryos from a different strain of mouse and implanted them in host mothers. In a very small number of the animals that resulted, the defective gene was incorporated not only into body cells but also into eggs and sperm that enabled the adult to pass the defect along to its offspring. Such mice are comparable to human carriers of the gene.

When animals carrying one copy of the defective gene were mated with each other, one out of every four offspring contained two copies of the defective gene and developed CF. These mice, the first of which were born in May, were smaller and less robust than their littermates.

The affected mice rapidly develop intestinal blockages similar to those found in human babies with the most severe forms of cystic fibrosis, preventing them from obtaining adequate nutrition from their food.

In contrast, the animals do not develop the severe lung-clogging mucus observed in humans, even though the lungs do show other signs of illness. But the North Carolina researchers note that children with cystic fibrosis have normal lungs at birth. They speculate that the intestinal blockage may be killing the mice before they have time to develop infected lungs. The researchers hope to find a treatment that will keep them alive long enough for the lungs to develop more severe symptoms.

Koller noted that some of the animals will soon be transferred to the Jackson Laboratory in Bar Harbor, Me., a commercial mouse-breeding facility. With support from the Cystic Fibrosis Foundation, Jackson Labs will then make the animals available to other researchers for the cost of breeding.