Gene therapy for cystic fibrosis patients.

Three teams of scientists received approval last week from a national panel of physicians and ethicists to administer gene therapy to a limited number of adults with cystic fibrosis -- the most common lethal hereditary disorder in the United States.

The National Institutes of Health's Recombinant DNA Advisory Committee (RAC) voted to allow each team to squirt solutions of genetically engineered cold viruses into the nasal passages and lungs of patients. The scientists hope the viruses will ferry corrected copies of the defective gene that causes cystic fibrosis into patients' airways, reducing production of the thick, lung-clogging mucus characteristic of the disorder.

Cystic fibrosis is most prevalent among whites, striking one of every 2,000 white children born in the United States. Patients experience recurrent lung infections and difficulty breathing because of mucus accretions in the lungs. In some patients, mucus builds up within the pancreas, intestines, or sperm ducts as well, leading to nutritional deficiencies or male sterility

There is no effective treatment. for cystic fibrosis, although physicians are testing several mucus-dissolving drugs. Most patients rely upon daily physical therapy to dislodge lung mucus and antibiotics to prevent infections from occurring within mucus-clogged organs. Nevertheless, few individuals with the disorder survive past age 30.

For years, the exact cause of cystic fibrosis remained a mystery Most researchers suspected it had something to do with the body's regulation of salt, because people with the disorder have abnormally salty sweat. Within the past three years, however, researchers have identified the gene that, when damaged, causes cystic fibrosis (SN: 9/2/89, P. 149). They have also found that the gene -- called the cystic fibrosis transmembrane conductance regulator (CFTR) -- normally codes for the production of a tunnel-like protein through which cells excrete salty chloride ions (SN: 3/2/91, p. 132). When mutated, the gene produces a protein that fails to do the job, creating instead conditions favorable to mucus deposition.

In the new gene therapy experiments, researchers will attempt to correct this defect by inserting functional CFTR genes into cystic fibrosis patients. The three research teams -- led by Ronald G. Crystal of the National Heart, Lung, and Blood Institute in Bethesda, Md., and two Howard Hughes Medical Institute investigators, James M. Wilson at the University of Michigan Medical Center in Ann Arbor and Michael J. Welsh at the University of Iowa College of Medicine in Iowa City -- plan to use similar approaches.

First, they will place working CFTR genes inside disabled adenoviruses, which can cause cold symptoms. Because adenoviruses have a specific affinity for the epithelial cells lining air passages in the nose and lungs, the researchers expect them to deliver the genes only to those cells. Disabling the adenoviruses prevents them from multiplying once inside the cells and causing disease.

Each team plans to test the gene therapy in roughly 10 patients over the age of 21 with mild to moderate cystic fibrosis symptoms. Crystal's and Wilson's teams will spray up to four teaspoons of CFTR-containing adenoviruses into the patients' nasal passages and, later, directly into their lungs. Welsh's team plans to squirt the viruses only into patients' noses.

The primary goals of the tests are to determine the safety of administering such gene therapy to cystic fibrosis patients and to find out whether the therapy enables patients' cells to produce functional CFTR proteins. Crystal says the procedure "offers the possibility, albeit low, of clinical efficacy"

However, Crystal cautions that any benefits derived from the therapy will last only a period of months, because the adenoviruses will not insert CFTR genes permanently into the genetic material of the patients' airways. If the initial tests are successful, the teams may ask the RAC for permission to readminister the treatment to the patients later on.

"We're very excited about the prospects of these experiments," says Robert K. Dresing, president of the Cystic Fibrosis Foundation. He adds that cystic fibrosis patients "should be extremely encouraged by the speed with which things are going ... this could have a real effect on their lives."

All three research teams plan to begin gene-therapy tests as soon as they receive approval from the Food and Drug Administration and NIH Director Bernadine P. Healy "We could start as soon as early 1993," says Wilson.