Novel Gene Therapy Approach Shows Promise for Cystic Fibrosis
07:31 p.m Apr 08, 1999 Eastern

STANFORD, Calif.--(BW HealthWire)--April 8, 1999--In a first of its kind clinical trial, Stanford researchers have begun using an aerosol gene therapy delivery approach to treat patients with cystic fibrosis.

They hope that the new treatment will offer patients an effective alternative to the daily regimen of therapies they must currently receive.

The new therapy involves inhalation of an aerosol containing millions of viral particles, each carrying a functional copy of the gene that -- when defective -- causes cystic fibrosis. The researchers believe that this replacement gene will make a corrected version of the abnormal protein involved in the development of lung damage in cystic fibrosis patients.

The most common fatal genetic disease among Caucasians in the United States, cystic fibrosis affects some 30,000 children and young adults, with nearly 1,000 new cases diagnosed each year. People who suffer from the disease must endure a myriad of daily medications to control their condition, which is characterized by the formation of thick mucus that can clog the lungs and lead to fatal infections.

The researchers hope that the new gene therapy approach can be developed into a less-onerous treatment, to be administered every several months or so.

The new airborne medicine takes about an hour to be delivered to the lungs via a plastic tube in the mouth. At this stage, Richard Moss, MD, professor of pediatrics at Stanford University School of Medicine, and his team are primarily testing the safety of the new method and are only administering a single dose. They believe that this will be sufficient for the viral particles to infect a population of lung cells and unload their precious cargo.

In the future, the researchers envision a repeat dose every eight to 12 weeks. This time period corresponds to what researchers believe to be the average life span of a lung cell, and repeated treatments at this interval will ensure sustained expression of the introduced gene.

First Patient

The doctors are looking at this not as a cure but as a maintenance treatment to try to prevent any further lung damage from occurring, said John Sharbrough, the first clinical trial patient to receive the treatment. The 29-year-old San Bruno, Calif., man said he considers himself lucky to be the first patient to inhale the tiny virus with its therapeutic baggage.

Sharbrough added that he found the gene therapy procedure only slightly more onerous than the twice-daily aerosol treatments he currently endures. "I'm really, really encouraged," he said of the new approach.

Sharbrough's participation in the clinical trial stemmed from his involvement in a previous Stanford study using the same gene therapy medicine. In that 1996 study, the gene-carrying viruses were delivered to the sinuses of patients.

According to the researchers, the sinuses of cystic fibrosis patients become inflamed and show clinical features similar to those seen in the lungs so they are a good model for testing new therapies. The sinus tissue is also much more accessible than lung tissue.

In the sinus study, Moss and his colleagues showed that the adeno-associated virus being used to carry the replacement human gene was safe -- it did not provoke an immune response in people. Results from the study indicated that inflammation was reduced in sinuses treated with the drug while sinuses treated with a placebo remained inflamed.

"The strategy was to take what we've learned and then go to the lungs," said Moss, who was a member of the sinus study team and is also leading the present clinical trial.

Current trial

The current study is a phase I clinical trial primarily designed to confirm the safety of the technique and to determine the most effective dose. As the trial progresses, the dose administered will increase ten-fold at each round.

Three patients will receive the gene therapy medicine at each dose level. Provided that each patient successfully tolerates the treatment, the dose will be increased and administered to a new trio of volunteers until data from a total of 12 patients have been collected. Based on the results of the sinus study, researchers expect that the higher doses will be most effective.

"The main thing is to make sure that people are staying healthy as we move through the doses," said Moss. "It all looks fine for the first three (patients)."

At two-week, one-month and three-month intervals following their treatment, each patient will return for a bronchoscopy -- a procedure used to gather a sample of the cells that line the airways -- so that the researchers can evaluate the effect of the treatment.

Samples are tested in Moss's laboratory and are also sent to Seattle to be analyzed by scientists at Targeted Genetics Corp., the company that manufactures the virus for cystic fibrosis gene therapy and has been working with Stanford to test it.

The researchers look for evidence that the replacement human gene has found a home in the patient's lung cells and that this gene is now making a corrected version of the protein that is malformed in the tissues of cystic fibrosis sufferers.

Defective protein

In healthy people, this protein -- cystic fibrosis transmembrane-conductance regulator (CFTR) -- forms a channel that allows water and electrically charged ions to pass in and out of cells. Lung cells must maintain a careful water balance to produce the slippery mucus needed to carry dust and invading microbes up and out of the lungs.

In cystic fibrosis patients, this protein is defective, causing the channel to become blocked. The thick, sticky mucus that builds up because of the blocked channel allows bacteria to thrive, leading to infections and lung destruction.

Both copies of the CFTR gene are defective in cystic fibrosis patients. People with only one copy of the abnormal gene will remain healthy, but they will be genetic carriers of the disease. If two carriers conceive a child, the baby has a 25 percent chance of being born with cystic fibrosis and a 50 percent chance of being a carrier of the disease.

It is the uncertain plight of these carriers that indirectly has inspired Sharbrough to participate in clinical trials that may lead to new treatments for cystic fibrosis.

"I have an older sister that died of CF 4 years ago and she has a daughter turning 10 that doesn't have it, but we know she has to be a carrier," he explained. Sharbrough is hoping that new therapies for cystic fibrosis will benefit his niece should she eventually have a child with cystic fibrosis.

Other Stanford researchers involved in this study include Phyllis Gardner MD, senior associate dean of education; Carol Conrad, MD, pediatric pulmonary staff physician; Ann Harkins, FNP, PhD, pediatric pulmonary clinical research coordinator; Zoe Davies, PNP, pediatric pulmonary clinical research associate; Ilynn Nepomuceno, pediatric pulmonary clinical research assistant; and Yao-Pi Hsu, life science research associate.

Collaborating scientists from Targeted Genetics include Barrie Carter, PhD, Darrell Salk, MD, David Sloane, PhD, and Tom Reynolds, MD, PhD.

Funding for the study was provided by Stanford's NIH-funded General Clinical Research Center, Targeted Genetics, Cystic Fibrosis Research, Inc., the Ross Mosier Fund and the Berger Raynolds Gene Therapy Fund.

The University of Washington is also involved in the clinical trial and Harvard University is expected to join soon.

Photography: A photo of patient John Sharbrough receiving the gene therapy treatment can be obtained by contacting Walter Hangad, 650/723-7897 (whangad@stanford.edu)

Patient interviews may be possible to arrange.

Copyright 1999, Business Wire

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