Stanford Launches Cystic Fibrosis Gene Replacement Therapy Trials.

STANFORD, Calif.--(BUSINESS WIRE)--Dec. 15, 1995--A 20-year-old Santa Rosa woman will be the first patient in a unique Stanford University Medical Center study of gene replacement therapy for cystic fibrosis.

Healthy cystic fibrosis (CF) genes will be sprayed into one of her maxillary sinuses on Saturday, Dec. 16, at Lucile Salter Packard Children's Hospital. The other sinus will receive a different dose a month or two later.

An escalating series of stronger doses will be administered to five more patients over the six-month trial, which will use a new viral vector developed by Targeted Genetics Corp. of Seattle, Wash., to carry the genes to where they are needed.

The new genetic material should replace faulty CF genes that cause thick mucous buildup that can lead to infections and death, said Dr. Phyllis I. Gardner, associate professor of molecular pharmacology and medicine, and principal investigator of the study.

It's a landmark study for Stanford, for cystic fibrosis and for gene therapy, said Gardner. The study is designed specifically to overcome obstacles that have led to failure in other CF gene therapy trials with other vectors.

"It's pioneer work," said Gardner. "The team has made some basic discoveries at the molecular level, done some clinical studies, and now we may have a completely novel way to treat this disease." It is the first time genetic replacement has been attempted in the sinuses of CF patients, and only the second human genetic replacement trial at Stanford. The modified adeno-associated viral (AAV) vector from Targeted Genetics has only been used in one other patient to date, she said.

(The first human gene trial at Stanford, focusing on cancer, started earlier this month; and a CF trial with this vector, but delivered to lungs and the nose, started last month at Johns Hopkins University in Baltimore.)

Animal studies with this vector have been promising, and have shown no major toxic effects. CF, the most common fatal genetic disease among Caucasians in the United States, afflicts 30,000 Americans. It is due to a faulty gene for transferring salts across cell walls which causes mucous buildup in the tissues, particularly the lungs. Infections lead to early death, usually by age 30. There is no effective treatment.

The Stanford CF trial is in two phases: Phase One, with a total of six adult patients, will look at safety. If all goes well, Phase Two will study effectiveness in up to 50 patients.

Gene therapy for CF has been largely ineffective to date.

Earlier attempts at CF gene replacement -- in the nostrils or the lungs -- have been disappointing: not enough healthy genes have been transferred to change the disease, or the patient's immune system has attacked and destroyed cells containing the replacement genes, said Dr. John Wagner, co-investigator and clinical fellow in pharmacology at the Stanford General Clinical Research Center, who will perform the gene transfer studies.

The Stanford team hopes to succeed by using a different site for the therapy, and a different vector to import the new genes.

Sinuses as the site

Earlier unsuccessful CF studies were done in the nostrils or lungs. The Stanford team chose the maxillary sinuses (below the eye) for this study for safety and convenience: The surface is the same tissue as the lungs, but the site is small and easily accessible. The treatment can be contained, and two different doses can be studied very precisely in one patient. "We can do two tests in one patient -- ultimately, patients will act as their own control," said Wagner.

Most CF patients suffer from sinusitis infections resulting in sludge-like mucous buildup. Many have had a procedure called canalization, or antrostomy, which makes it easier for sinuses to drain and to be examined or biopsied.

Gene therapy research in the lungs is difficult to confine to a small area, and requires a more invasive procedure than on the sinuses, said Wagner.

AAV as the vector

Wagner said the two major problems with earlier gene transfer trials were due to effects of the viral vector that was used to convey the genes.

A vector is needed to import the healthy genetic material into the cells. Prior trials have used an adenovirus, which is one of the causes of the common cold. The problem was that the viral material caused inflammation in the respiratory tissues, before enough genetic material was transferred.

The new AAV vector from Targeted Genetics is a parvovirus which alone is not known to cause disease or irritation. It has been disabled so it can't reproduce itself.

Since AAV may not activate the immune system, the sinuses may absorb more healthy genes and the genes may remain active longer.

This type of gene therapy will not be a one-stop fix-it, Wagner cautioned: healthy genes need to be "installed" on a regular basis, since the virus that carries them has been intentionally crippled. "It's a fancy medication -- a DNA drug," he said.

Each gene-carrying virion will change only one sick cell, so it takes a great deal of the genes and the virus, Wagner said.

However, only 5 to 10 percent of the patient's CF genes need to be replaced, because the cells all connect electrically. One working cell electrically affects many others, Wagner said. Gardner is optimistic the study result can be applied to the lungs. However, if it works only in the sinuses, it will still be a success, she said. "It might be a therapy for sinus disease in cystic fibrosis."

The project has been subject to rigorous approval and regulation from several agencies and committees including the Food and Drug Administration, the National Institutes of Health Recombinant DNA Advisory Committee, and the Stanford University Biosafety Committee and the Human Subject Committee. The adult participants signed informed consent forms; "Safety -- of the subjects, their families, and health care workers -- is our primary concern," said Gardner.

Among collaborators on the project are Jeffrey Wine, professor of psychology and director on the Cystic Fibrosis Research Laboratory; Dr. Richard Moss, professor of pediatrics and director of the Cystic Fibrosis Clinic at Lucile Salter Packard Children's Hospital; and Dr. Mary Lynn Moran, an ear, nose and throat specialist and Stanford clinical instructor of surgery; Barrie J. Carter, vice president and director of research and development at Targeted Genetics.

Funds for the project come from the National Institutes of Health grants, the Stanford General Clinical Research Center, Cystic Fibrosis Research Inc., and a private donor at Lucile Salter Packard Children's Hospital. Targeted Genetics has supplied the viral vector without charge. -0-

Note to Editors: For Comment: At Stanford, Dr. Phyllis Gardner 415/723-6086 or 725-5088; or Dr. John Wagner, pager: 415/ 723-6661 (ID# 2290). At Targeted Genetics Corp. in Seattle, Alberta Garvin, 206/521-7824. Patient Leah Sauer can be available for interviews: 707/542-3048.

CONTACT: Stanford Medical Center

Judith Horstman, 415/498-6333 or 723-6911