Donavon Decker arrives at Ohio State University with his mother, Ruth Weber

The evening of Sept. 2 was memorable for neurologist Jerry Mendell of Ohio State University in Columbus, for gene therapy specialist Jim Wilson and surgeon Hansell Stedman of the University of Pennsylvania in Philadelphia, and for air traffic controller Donavon Decker of Huron, S.D., who has limb-girdle muscular dystrophy (LGMD).

That night was also a milestone for dozens of MDA research grantees who, along with MDA-supported researchers Mendell, Wilson and Stedman, have been working with culture dishes and mice to develop gene therapy for muscular dystrophy for more than a decade.

On that evening, just hours after passing its final regulatory hurdle in Washington, a clinical trial to test the safety of gene transfer in LGMD began.

The procedure "went like clockwork," Mendell told reporters immediately afterward.

Decker, 36, was given an injection into a foot muscle of billions of genes for alpha-sarcoglycan, a key muscle protein that's missing in Decker's muscles because of a genetic flaw. (For more on gene therapy for muscular dystrophy, see the gene therapy section of Quest, vol. 6, no. 4.)

SAFETY FIRST

"I was very excited; it's kind of been a long waiting period, but this is the first step [toward] the cure," Decker said shortly after finding out that he had been chosen to go first in the historic trial.

"I went from not knowing if there would ever be a cure to where we think now that it's just right around the corner."

The investigators say that while a cure might not exactly be "right around the corner," it's a lot more realistic to talk about it now.

"We're hopeful about the results of this pilot study," Mendell said. "But we want everyone to know it's only a first step. We don't expect Donavon or any other patient to directly benefit from this first trial, which is designed primarily to determine the safety of the procedure.

"However, we do expect that, if all goes well, we'll be injecting more patients soon, and that eventually we'll be looking at whether gene therapy can effectively stop the progression of muscular dystrophy."

THE GOAL: MENDING THE MEMBRANE

Before the injection, neurologist Jerry Mendell explains to Decker what will happen.

Six to 12 people will participate in this first (phase 1) LGMD safety trial. Each has a defect in a sarcoglycan gene that causes one of four sarcoglycan proteins to be nonfunctional. (To be precise, each person has two defects, one in each of two genes for a sarcoglycan protein. People with one defect are considered LGMD carriers.)

Normally, there are four sarcoglycans -- alpha-, beta-, gamma- and delta-sarcoglycan -- embedded in the muscle cell membrane (a thin sheath around the cell), helping to keep the membrane together during the stress of muscle contractions and perhaps serving other roles important to the cell's function. If any of these proteins is missing, all four sarcoglycans generally fail to function and adjacent proteins in the membrane can also be affected.

The researchers will be checking Decker's foot muscle by taking a biopsy six weeks after the injection. They'll look for adverse effects, including evidence of an unwanted immune response to the gene transfer, and they'll also look at whether the needed proteins are in the cell, particularly whether they're in the membrane.

There are several obstacles to effective gene transfer. A formidable one has been the immune system, which is designed to keep foreign material out of the body.

The genes Decker received were injected with a highly modified virus that, in animal studies, has been shown not to provoke much of an immune response.

The virus, known as adeno-associated, or AAV, has also been rendered incapable of replicating itself in the body and causes no known human illness even in its natural state.

OVERCOMING OBSTACLES PART OF LIFE FOR DECKER

Obstacles may worry the research community, but overcoming them is nothing new for Decker.

"When he applied with the Federal Aviation Administration, he was denied employment, as it was determined his disability would prevent him from properly performing his duties and could possibly jeopardize aviation safety," wrote Air Traffic Manager Alvin Johnson in a 1995 letter supporting Decker's nomination for an MDA State Personal Achievement Award.

Mendell prepares the gene injection for Decker, while surgeon and gene therapy investigator Hansell Stedman (center) stands by.

"Not accepting this, he wrote several letters to congressmen, had the decision overturned and started his chosen career. Since coming into the FAA, Donavon has earned the respect of his peers because of the positive way he accepts and deals with his handicap. He is also an excellent specialist and an asset to the Huron Automated Flight Service Station." Decker got the award.

Today, he's still able to walk but with difficulty, and he has trouble opening heavy doors and climbing in and out of vehicles. However, he continues to excel in his work.

NEXT STEPS

In about a year, the investigators will know more about where to go with phase 2. This phase will likely answer more questions about muscle function and will likely involve injection of genes into a larger muscle.

Eventually, systemic delivery of the genes will probably be necessary to achieve meaningful functional improvement in most people with muscular dystrophy.

Participants for phase 1 of this trial have been selected, and the research team is compiling a database of people with LGMD to be considered for phase 2.

To get involved, visit MDA's Web site at www.mda.org (check under "What's New" or "Research/Active Clinical Trials") or call MDA at (800) 572-1717.