Gene Therapy Offers Hope for Cystic Fibrosis

Two groups of researchers have independently corrected the biochemical defect that causes cystic fibrosis by inserting a healthy gene into diseased cells grown in the laboratory, a major step toward developing new therapies for the disease.

The new findings announced Thursday in articles in the journals Cell and Nature suggest it may be possible within a few years to cure the disease either by replacing the defective gene with a healthy one through gene therapy, by delivering an intact protein to the diseased cells or by the development of new drugs.

“We’re not talking decades, we’re talking years, a few years,” said Robert J. Beall, medical director of the Cystic Fibrosis Foundation. “We’re very excited.”

“These papers rank among the most important publications in the foundation’s history,” added Robert K. Dresing, the foundation’s president.

Researchers discovered the genetic defect that causes the disease only a year ago. Thursday’s announcement indicates that the discovery has greatly accelerated the pace of research on the disease, which affects one in every 1,800 children, impairing breathing and cutting life short.

The possibility of gene therapy for the disorder has become even more intriguing because the first efforts at human gene therapy were finally begun last week at the National Institutes of Health. After suffering years of obstacles and setbacks, researchers there began treating a child with another genetic defect called adenosine deaminase deficiency.

Success of that treatment, or at the very least a demonstration that it does not have any adverse side effects, is expected to pave the way for experiments with other proposed therapies, such as for cystic fibrosis. “I think we have reason to be very optimistic,” Beall said.

In more general terms, the new findings also reflect the greatly accelerated increase in knowledge about a wide range of genetic diseases. In recent months, researchers have also discovered genetic defects that cause one form of arthritis, neurofibromatosis, myoclonic epilepsy and a form of kidney disease called Alport syndrome, among others.

Also this summer, researchers began studies in humans of a new form of therapy for Duchenne muscular dystrophy based on the recent discovery of the defective gene that causes that disorder. These results and others still in the laboratory stage suggest that intensive efforts over the last decade to understand genetic diseases are beginning to bear rich fruit in therapeutic applications.

The defective gene that causes cystic fibrosis is one of the most common in nature. It is carried by one in every 20 whites--about 12 million Americans in all. When two carriers marry, each child has a 50% risk of inheriting the gene from both parents and developing the disease.

The disease is marked by a buildup of mucus in the lungs and the upper respiratory tract that impairs breathing and leaves the victims susceptible to respiratory infections. It also affects the pancreas in about 75% of victims, blocking secretion of enzymes necessary for digesting and absorbing fats in the diet.

The symptoms arise because defective cells are not able to properly secrete salt and water through pores called chloride channels. Instead of a thin film of water that is important for cleansing the lungs, for example, the defective cells produce a thick mucus that traps bacteria and viruses that can cause infections.

Earlier in this century, cystic fibrosis was uniformly fatal, killing most affected children during their first year of life. The development of antibiotics to control lung infections and the adoption of nutritional therapies have extended the median life span of cystic fibrosis patients to about 26 years, and many live into their 30s and 40s.

But there is no effective therapy for the disorder itself.

The two groups--one headed by internist Michael J. Welsh of the University of Iowa College of Medicine and molecular biologist Alan E. Smith of Genzyme Corp. in Framingham, Mass., the second by geneticists Lap-Chee Tsui of the Hospital for Sick Children in Toronto and Francis Collins of the University of Michigan--used slightly different techniques to achieve the same goal.

Tsui and Collins, who discovered the defective gene last year, worked with test tube-grown pancreas cells from a cystic fibrosis patient who lacked a key protein. They inserted a gene from healthy cells into a virus that carried it into the defective cell’s nucleus, where it became integrated with the cell’s own genes and began producing the protein. The cells could then secrete salt normally.

Welsh and Smith used a different virus to insert the cell and they worked with cells from the respiratory tracts of cystic fibrosis patients, but their results were identical: The cells could function normally.

Researchers cautioned that many questions must be answered before similar gene therapy could be attempted in humans. “Which cells do you put it into,” asked Welsh. “Do you have to have it in all the cells? What happens if you get too much of the protein? Are there any side effects?” These questions must be studied in animals before human studies can begin.

Meanwhile, Smith and his colleagues at Genzyme are working on an alternative approach. Instead of inserting a healthy gene into the cells so that the cells themselves can produce the protein, they hope to administer the protein at intervals directly into the lungs and respiratory tract. Although this would constitute a more short-term approach, it would have the advantage of sidestepping some of the ethical and moral questions of altering genetic makeup.

The problem is that it is more difficult to get a protein inside a cell than it is to insert a gene, but he hints that it may be possible. “That’s something people have thought about a lot in the past,” Smith said. “I wouldn’t deny that it’s a difficult problem, but there are approaches that might work.”

Finally, now that researchers have identified the defective protein that causes the disease, it may be possible to use traditional pharmaceutical approaches to design drugs that would improve the protein’s function. Such drugs might greatly ameliorate the symptoms of the disease.

Beall predicted that it will be a race among researchers using the different approaches to see who can be successful first.

Others who participated in the research included molecular biologist James Wilson of the University of Michigan and Ray Frizzell of the University of Alabama.