UF Researchers Say Gene Therapy Method For Treating Cystic Fibrosis Appears Safe

July 22, 2003

GAINESVILLE, Fla. — Gene therapy using a common harmless virus to insert corrective DNA into malfunctioning cells in the lungs of cystic fibrosis patients appears safe, say University of Florida researchers.

Findings from a study published July 20 in the scientific journal Human Gene Therapy clear the first major hurdle in the extensive process of developing a treatment for cystic fibrosis, an incurable inherited disorder in which a defective gene causes the body to produce an abnormally thick, sticky mucus that clogs the lungs and leads to life-threatening pulmonary infections. The study was designed to test the safety of the gene-carrying virus at therapeutic doses, rather than the gene’s effectiveness in reversing cystic fibrosis.

Scientists at UF, the Johns Hopkins University and Targeted Genetics Corp. packaged the adeno-associated virus, or AAV, with a healthy version of the gene that, when defective, causes cystic fibrosis. They then administered the solution to 25 cystic fibrosis patients. UF researchers found the virus to be safe in earlier studies with human patients, but whether it remained so once the dose was increased to a level needed to transfer the corrective gene had never been studied.

UF researchers first modified AAV for use as a gene-transport molecule, or vector, in the early 1980s. It now is patented, and scientists worldwide have modified versions of it for developing treatments for different diseases.

“Safety is always the first concern in any new drug or therapy, but even more so in gene therapy, where there have been complications related to the means used to deliver the gene,” said Dr. Terence Flotte, a veteran gene therapy researcher and chairman of the UF College of Medicine’s pediatrics department. “The concept of changing genes seems kind of scary, but in fact any major complications from gene therapy have been related to the carrier system rather than the gene. The key issue here was pushing the dose up to a range where we might see an effect.”

Cystic fibrosis, the most common hereditary disease in the United States, destroys the lungs through recurrent infections. It is caused by a faulty gene that impedes the normal passage of salt and water through the body’s cells. It affects an estimated 25,000 to 30,000 Americans, with only half surviving past age 30.

In the UF/Johns Hopkins study, which began in 1995, cystic fibrosis patients started out receiving small doses of the gene therapy solution, which were increased incrementally as the study progressed. Physicians dripped the solution through small tubes inserted into the lower lobe of the right lung and one nostril in each of the volunteers, who at the start of the study ranged in age from 15 to 43.

All of the participants experienced adverse effects such as back pain, sinusitis, headaches and pneumonia during the study. But by carefully looking at the medical histories of study participants, the typical complications caused by cystic fibrosis and the occurrence of adverse effects in relation to the times of AAV administration, researchers determined these effects were not caused by the presence of AAV or the corrective gene.

Previous gene therapy studies conducted at other institutions used adenovirus, which has been linked to complications such as inflammation. Its use and the way in which it was delivered precipitated the Sept. 17, 1999, death of a young study volunteer at the University of Pennsylvania’s Institute for Human Gene Therapy, Flotte said.

“Despite its similar name, AAV is in an entirely different class of virus than adenovirus, and unlike adenovirus, AAV does not cause inflammation,” Flotte said. “What we’ve done here is use a virus that has probably infected 90 to 95 percent of us and never caused a disease, and when we alter it by putting in a healthy gene, it still doesn’t appear to cause any diseases or toxicity. And we delivered it very selectively so that any complications that might occur would be localized.”

Now that AAV’s safety appears established, researchers are beginning to look at this method’s effectiveness in treating cystic fibrosis.

“We’ve gone on and been involved in trials where the virus with the healthy gene is inhaled through a nebulizer and enters both lobes of the lungs,” Flotte said. “These additional subjects have not shown any side effects, and the encouraging preliminary results indicate there is some beneficial effect on lung function and inflammation.”

This study complements other similar gene therapy trials and validates AAV’s safety for use in humans, said Dr. Richard Moss, a professor, chief of pediatric pulmonary medicine and director of The Cystic Fibrosis Center at Stanford University.

“Dr. Flotte’s study is particularly important in that the gene vector was well tolerated after being instilled directly onto lining surfaces of the nose and lung,” he said.

The study was sponsored by Seattle-based Targeted Genetics Corp. and overseen by the U.S. Food and Drug Administration’s Center for Biologics Evaluation. The National Institutes of Health and the Cystic Fibrosis Foundation also provided support.