Leading the Fight Against Cystic Fibrosis

BY HEATHER ROCK WOODS

FALL 2001 - Thirteen-year-old Molly Stroud Pam of Menlo Park is a typical teenager who goes to middle school, dances twice a week, and plays basketball. But she also spends one to two hours a day undergoing treatment for cystic fibrosis, which includes a lengthy regimen of medications and physical therapies. She had to cancel a trip to England this summer because a severe lung infection landed her in the hospital for several weeks.

Dr. Richard Moss, director of Packard's Cystic Fibrosis Center, monitors patient Molly Stroud Pam's lung infection during a two-week stay at Packard in 2001.

"She was brokenhearted about the school trip, but she knew it was that or live a long life," says Molly's mother, Penny Stroud. "Everyone in the cystic fibrosis community is hopeful that some day scientists will unlock something to keep our children's health from declining."

Molly's doctor, Richard Moss, M.D., is optimistic that such a day is not far off. He and his team at the Cystic Fibrosis Center at Lucile Packard Children's Hospital conduct groundbreaking research that aims to find better treatments and, ultimately, a cure.

"Through clinical trials, I'm sure we'll become aware of powerful treatments in the next three to five years to make cystic fibrosis a more stable chronic disease that is easier for patients to control," says Moss, director of the Center and professor of pediatrics.

Translating Basic Science to New Treatments

The Center is currently running or planning a dozen such clinical trials as the newest member of the Therapeutic Development Network, a national collaboration of eight preeminent research centers whose goal is to rapidly design and conduct clinical trials. The Cystic Fibrosis Foundation asked Stanford to join the network because of the university's renowned work translating basic science into innovative treatments. Stanford has longstanding expertise in areas such as immunology, gene therapy, cystic fibrosisrelated osteoporosis and diabetes. Researchers at Stanford also are using a high-resolution chest scanning procedure that promises to enhance the understanding and treatment of cystic fibrosis.

By pooling resources and expertise, the national network can run clinical trials with sufficient numbers of participants -- often a challenge for an individual site -- and use standard criteria in conducting each trial. These factors expedite studies and produce more meaningful results.

Cystic fibrosis is the most common life-shortening genetic disease among Caucasians in America. Some 30,000 Americans have two mutated copies of the cystic fibrosis gene. As a result, their bodies make defective channels for chloride (salt) to enter or leave cells, creating a salt imbalance and a thick, sticky mucous that smothers the lungs and other organs. The protein made by the gene, CFTR, also controls several other crucial cell functions.

Harmful bacteria thrive in the mucous and provoke unchecked inflammatory responses that damage lung tissue.Major symptoms of cystic fibrosis include persistent coughing, wheezing, and pneumonia. Children may eat heartily but grow poorly because the mucous blocks the pancreatic ducts that deliver digestive enzymes.

Increasing Lifespan

During the 1980s, the average lifespan for a cystic fibrosis patient increased from approximately 18 to 29 years, largely due to the ability to control infections and to improved nutrition.

In the last decade, the average age crept to 32 years, but two drugs introduced since then are beginning to significantly affect longevity and create better health.

"In the 20 years I've been involved with cystic fibrosis, there's been an amazing change,"Moss says.

Now the Cystic Fibrosis Center is able to treat infections more aggressively and sees better outcomes. Patients regularly see a team of care providers, including a nutritionist, respiratory therapist, and social worker. The specialized, interdisciplinary care that cystic fibrosis centers provide results in better overall health, Moss says.

Packard Hospital and Stanford University Hospital treat 350 patients a year, more than any of the other hospitals in the state. This number includes more than 100 patients who are evaluated for lung transplants. Patients with cystic fibrosis comprise the largest group -- 40 percent -- of all lung transplant candidates at Stanford.

As a hopeful sign of things to come, almost half of the Center's patients are adults. Two years ago, the medical school hired Noreen Henig, M.D., to direct the new adult cystic fibrosis program, which provides continuity as patients move from pediatric to adult medicine and become responsible for adhering to their medical regimens.

Right now, complying with treatment is no easy task. Patients often need 10 to 15 medications a day to thin mucous, control infections and inflammation, open airways, and replace blocked digestive enzymes and vitamins. In addition, they need to cough up the infected mucous from their lungs daily with various chest physical therapies. And, periodically, they spend a few weeks in the hospital receiving intravenous antibiotics to reduce dangerous bacteria levels, allowing lung function to recover partially.

Gene Therapy Trials Hold Promise

Some therapies being studied could make treatment less frequent. For example, monthly gene replacement therapy could replace most of the daily drugs.

Packard began cystic fibrosis gene therapy trials in 1996 with the first study to spray the harmless adeno-associated virus (AAV) vector carrying healthy copies of cystic fibrosis genes into the sinus cavities. The trial found that the virus safely delivered the genes into sinus cells. Additionally, the study produced evidence of the cells making normal channels for chloride transport and of reduced inflammation.

Now the Center is testing the safety and efficacy of the same therapy in the lungs with the first use of multiple doses with the AAV gene carrier. Patients 12 and older inhale a dose of normal cystic fibrosis genes once a month for three months. Multiple doses are necessary for long-term treatment because lung cells die every two to three months and are replaced with cells containing the cystic fibrosis defect.

In another ongoing trial, participants inhale gamma interferon, a natural body chemical to try to reduce the inflammation in the lungs by stimulating the immune function of the normal defense cells."We view the defensive system as out of balance, and this is an attempt to correct it. This trial represents an entirely new approach to cystic fibrosis therapy,"Moss says.

Results from both trials are expected later this year. Major funding for the Center's trials comes from the Berger-Raynolds Fund, Donelson and Virginia Berger, the Hedco Foundation, the Ross Mosier Classic, the National Institutes of Health, the Cystic Fibrosis Foundation, and Cystic Fibrosis Research Incorporated. "We are pleased to support Dr. Moss' pioneering clinical trials and are excited by the promise it holds for children with this debilitating disease," says Donelson Berger.

Although it usually takes five years to move a drug from human testing to FDA approval, trials can affect treatment choices immediately. "When an early-stage trial recently showed better than expected outcomes from the use of an inhaled antibiotic in children under 6 years, physicians watchfully began prescribing the drug (already FDA-approved for older children and adults), and researchers accelerated the testing schedule,"Moss says.

For Molly Stroud Pam, and the tens of thousands of children and adults who currently live with cystic fibrosis, less cumbersome and more effective treatments are on the horizon with a promise for longer and healthier lives.