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Stanford Report, October 9, 2002

Gene therapy treatment may offer relief for cystic fibrosis patients


Researchers at the medical center have shown for the first time that gene therapy techniques may one day help patients with cystic fibrosis, a life-threatening inherited disease characterized by thick mucus buildup in the lungs. The mucus hampers breathing, fosters deadly infections, and causes ongoing lung damage. Patients who inhaled particles of a virus engineered to express a gene to correct the condition exhibited a significant, but temporary, clearing of their lungs after the first of three monthly treatments.

"The fact that we were able to increase pulmonary function, even transiently, is the first indication that any kind that gene therapy can work in cystic fibrosis," said Richard Moss, MD, professor of pediatrics and director of Lucile Packard Children’s Hospital’s Pulmonary Disease and Cystic Fibrosis Center. Moss presented the results of the phase-II multi-center trial at the annual North American Cystic Fibrosis Conference in New Orleans last week.

The result was unexpected because the double-blind, placebo-controlled trial was designed to test the safety of repeated high doses of the virus carrying the repair gene. The lungs of cystic fibrosis patients worsen over time, and the researchers thought even though the 37 participants had a relatively mild form of the disease, their average age (24) was too high to allow them to benefit from the treatment.

Cystic fibrosis patients had a significant yet temporary improvement in lung function after inhaling a virus (tgAAVCF) engineered to express a repair gene. The lung function of patients in the placebo group declined during the trial.

"We didn’t expect to see much change in pulmonary function in this group of patients at this stage of the disease," said Moss. "By the time a patient is an adolescent, they have so much lung damage that no therapy will be completely successful." Ethical considerations prohibited the researchers from testing the safety of the gene therapy in patients under age 12.

In the trial, the patients inhaled a mist containing 10 trillion tiny viral particles with each dose. The virus entered the lung cells and commandeered the cellular machinery to express the gene defective in cystic fibrosis patients: a membrane channel protein that maintains the balance of water and salts needed to produce the healthy lung secretions that trap and remove harmful bacteria. The monthly treatment was repeated three times.

"The patients’ safety was our primary concern," said Moss. After each dose the researchers monitored participants’ pulmonary function and sputum to ensure treatment wasn’t making the disease worse. They found no increase in adverse events in any of the treated group compared to the 17 patients who received a placebo, and they concluded that the gene therapy treatment was well-tolerated.

The researchers also saw two improvements in the treated group: within one month of their first treatment they were able to breathe more freely and they had reduced levels of a protein called IL-8 in their sputum. IL-8 induces an immune response that causes scarring in the lungs of cystic fibrosis sufferers.

The improvement in both pulmonary function and IL-8 levels, however, waned over time and by the end of the study the treated group was not significantly better than those who had received the placebo. Further research showed that the patients began to generate antibodies to the virus used to escort the gene into the cell.

"We don’t know if the antibodies are affecting the ability of the therapy to work, but these results suggest that that may be happening," said Moss. Despite this drop in efficacy, the researchers are still cautiously optimistic about the future of gene therapy for cystic fibrosis. Samples of lung cells taken from eight of the patients showed that a surprisingly large number of the cells sported the repair gene even 60 days after treatment.

"We found between 30 and 100 copies of the gene per cell, which is very encouraging," said Moss. The researchers were unable to confirm, however, whether any of the cells were actually making the protein. In vitro research suggests that only about 5 percent of the lung cells need to make the channel protein in order to slow or block the progression of the disease.

The researchers plan to conduct a short-term trial in a larger number of patients to confirm efficacy before beginning a phase-III trial of the treatment.

The trial was funded in part by the NIH and Targeted Genetics Corp. This company manufactures the adeno-associated virus containing the cystic fibrosis transmembrane-conductance regulator gene used in the study.

Novel therapy for cystic fibrosis enters clinical trials at Stanford (3/14/01)

In its race to rescue a child, Packard's pulmonary center draws on innovation (2/20/02)

New gene therapy approach shows promise for cystic fibrosis (4/7/99)