September 1, 2010 (Vol. 30, No. 15)

Cycling Group Shows that Exercise Provides Beneficial Effects to Cystic Fibrosis Patients

Translating the advances in cystic fibrosis (CF) gene-therapy research into the clinic hasn’t been successful. In fact, during the 21 years since the gene responsible for causing cystic fibrosis was discovered, and despite the early excitement about the possibilities of gene therapy, no gene therapy is even close to emerging.

Right now, one thing cystic fibrosis patients can do to improve their health is to exercise.

That point is hardly lost on noted gene-therapy researcher James Wilson, M.D., Ph.D. To help patients now, he formed Team CF, an elite mountain biking team composed primarily of women, as well as Club Team members spread throughout the U.S. The goal, as member Matt Holloway says, is to make “CF” stand for “Cure Found.”

The immediate goal, however, “is to use Team CF to promote fitness as beneficial to those with CF,” emphasizes Dr. Wilson, who is professor of pathology and laboratory medicine, gene therapy program, University of Pennsylvania School of Medicine. He is also editor-in-chief of Human Gene Therapy, a peer-review journal published by Mary Ann Liebert, Inc.

The youngest of the elite mountain bike racers, Kaitlyn Rose Broadhurst, has cystic fibrosis herself. A cross-country runner at Neumann University, the 21-year old was persuaded to compete in mountain biking during an internship for the Cystic Fibrosis Foundation. Elite team members trained her. She has competed in two races and won them both.

After each race, she says, “I’ve been approached by several people for information about the team or about joining it. A lot of people are surprised I’m even doing this.”

At Kaitlyn’s first race last July, Mallory, a CF patient and five-year old daughter of Matt Holloway, watched her closely.

“I told Mallory that Kaitlyn raced and won in her first-ever mountain bike race,” Holloway says. “She looked up at me and said, ‘That means that I could race mountain bikes.’ I said ‘yes,’ and then she said ‘and I could win medals too, Daddy!’ I said ‘You sure can!’

“To me, this is a two-part inspiration,” Holloway continues. “First, it gives my daughter a phenomenal role model, the knowledge that she can do things that are harder for her to do and be successful. Second, as a parent of someone with CF, it is the most encouraging thing to see another person exercising at a competitive level and be so healthy, all due to the fact that she exercises regularly and works just as hard as the healthy person next to her.”

Kaitlyn Rose Broadhurst (center), the youngest member of Team CF, has cystic fibrosis herself.

Good Beginning

That’s a start. Since 1981, researchers have begun proving the beneficial effects of cardiovascular exercise for cystic fibrosis patients. Several research centers throughout the U.S. now actively promote exercise. Its benefits include increasing cardiorespiratory function and oxygen consumption, and slowing the decline of lung function. But the main benefit may be its role in mobilizing the sputum that collects and hardens in CF patients’ lungs where it becomes a breeding ground for bacteria. By causing that sputum to move, it can be expectorated more easily, thus reducing the risk of infections.

Kaitlyn’s experience echoes the clinical reports. In college, she became less regimented about her treatments. Also, “I dropped off the track and cross-country teams for two years and my lungs got congested,” she says. When she rejoined the team, she noticed that, “The more I ran, the more I needed to clear my lungs.” With Team CF, that need to clear her lungs was even greater, she says, “so cycling encouraged me to do my therapy regularly.”

Team CF is more than just an elite mountain biking team, however. Since its formation in 2009, it has grown to include two regional road racing teams and a club (amateur) team of about 100 members that includes all ages. All wear the Team CF jersey and race independently, although the elite team focuses upon certain key races. They all have the job of creating an awareness that exercise benefits cystic fibrosis patients.

Funding Provided the Impetus

Dr. Wilson focused initially on mountain biking and women racers because neither is well-funded, “and I knew a few women cyclists who were pretty good,” he says. To get the attention of the cycling community, and therefore sponsors, he recruited elite competitors at the national and international levels, including Bicycling Magazine’s “Fit Chick” columnist Selene Yeager.

Yeager and teammate Cheryl Sornson have been accepted to compete next spring in the most severe and competitive mountain bike race in the world, South Africa’s Cape Epic. Team members won some national races last year, and Dr. Wilson predicts that several of his racers will win national titles this season, also.

“We had to be realistic about who to recruit and what we could afford,” Dr. Wilson says. A professional road bike team is a sophisticated operation and could cost millions of dollars. Team CF doesn’t have that. It does have a group of sponsors, though, that includes pharmaceutical company Eurand, medical supply company Hill-Rom, nutritional firm Infinit, mountain biking pioneer Gary Fisher, mountain biking coach Chris Eatough, bike manufacturer Trek, components manufacturers SRAM and Bontrager, and clothing company Verge.

“We’re aligned with three clinical programs—the Children’s Hospital of Philadelphia, the University of Massachusetts Medical Center, and Johns Hopkins Medical Center,” he adds, noting that his team has partnered with the Cystic Fibrosis Foundation, which is hosting “Eurand CF Cycle for Life” biking events in 18 American cities this year.

As Holloway says, “I think Team CF is raising awareness, but it is only touching the tip of the iceberg. Since it is in its first year, people on the race circuit are still getting to know the team.”

Recognition of the team and of cystic fibrosis will improve, he predicts, as team members participate in more races. The CF Foundation’s Cycle for Life events help, but they are aimed at fundraising. For example, the foundation’s first cycling event attracted 87 riders and raised $88,000—76% more than the goal.

Team CF, in contrast, focuses upon fitness. As Dr. Wilson says, “The younger you can start them off, the better they will be, so we’re focusing on getting CF kids and young adults active.”

In the 1980s and ’90s Dr. Wilson was a technical ice climber who biked during the summer to keep in shape. (He since has switched to endurance mountain biking, competing on the national racing circuit.)

In 1989, he also was a Howard Hughes Medical Institute principal investigator at the University of Michigan. “I was the gene-therapy guy, and shared a floor with Francis Collins, who discovered the cystic fibrosis gene,” he says. So, when Dr. Collins’ “eureka” moment came, Dr. Wilson was close by.

That collegial relationship and a quirk of fate catapulted Dr. Wilson into the search for a cure for cystic fibrosis. As he recounts, when a speaker at the Cystic Fibrosis Foundation’s annual meeting cancelled, Dr. Collins asked him to fill in. The plan, he says, was to give a conceptual talk about gene therapy.

By July, however, Dr. Collins told him, “We’re close to finding the gene.” By September, the discovery was announced in Science. “The whole concept of the talk changed from conceptual to practical.

“It was an immensely exciting time,” Dr. Wilson recalls. When he walked into the lecture hall in October, “The energy in the room was palpable. People were so excited about the cloning of the gene. I was hooked. I devoted my career to discovering a cure for CF.”

In September 1990, he demonstrated that a gene could be transfected into a viral vector to cure cystic fibrosis in a Petri dish, he points out.

About the same time, William French Anderson, M.D., began the first human trial of gene therapy, in an attempt to cure severe combined immunodeficiency in a four-year-old girl. Breakthroughs seemed imminent, and the cystic fibrosis community watched the research with great anticipation. Developing an effective therapy, however, would take a long and complicated path.

“Like many others in the 1990s, we were focused on clinical applications for gene therapy using existing vector technologies,” Dr. Wilson explains. “That technology, however, was not up to the task, so for the past seven years, we have refocused on identifying new technologies.”

His group discovered a new family of adeno-associated viruses (AAVs) in human and nonhuman primates that undergo substantial recombination in vivo, and is developing designer vectors based upon them.

He says approximately 1,500 preparations of the vectors are distributed each year, and his lab makes “six to ten international shipments per week.” Many of these vectors, he says, offer an improved option for delivering genes to the lung, which has been a long-standing challenge for cystic fibrosis gene therapy. He also has used lentiviral vectors “to achieve stable and long-term gene transfer in nondividing cells,” he adds.

The field is seeing other improvements, too. “John Engelhardt, Ph.D., director of the Center for Gene Therapy at the University of Iowa, has developed a ferret model for cystic fibrosis,” Dr. Wilson says. That model will be used to evaluate some of Dr. Wilson’s new vectors for gene therapy as well as “to understand how stem cells in the adult airway respond to injury resulting from dysfunction of CFTR.”

As researchers learn more about the genomic basis of CF, the disease appears increasingly complex, with links emerging between the severity of CF and the development of type 2 diabetes. As other CFTR mutations and modifier genes are examined, additional influences may be uncovered. As yet, exactly how the CFTR protein triggers the disease remains unknown.

“It’s ironic. I have spent 20 years trying to develop an elegant, broad approach (to curing cystic fibrosis). Now the one thing I can do to help individuals today is to encourage exercise!” Dr. Wilson says.

A density map of the AAV2 capsid surface viewed down a twofold axis of symmetry: Radial coloring begins at the base of the capsid (blue) and extends to the protrusions (red) surrounding the threefold axes of symmetry.

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