Jerry Mendell

Kevin Campbell

MDA-supported researchers and clinicians at the University of Pennsylvania in Philadelphia and Ohio State University in Columbus are poised for the first injection of a safety trial of gene therapy for a type of limb-girdle muscular dystrophy (LGMD). The final hurdle is a Sept. 2 review by a subcommittee of the National Institutes of Health. The historic injection could take place within hours of approval.

"I feel privileged to be participating in this important project," said Jerry Mendell, the neurologist who'll be administering the injection of a modified virus containing healthy genes to patients with LGMD at Ohio State. "After 30 years of working with patients with muscular dystrophy, I enter this endeavor with hope and cautious optimism."

LGMD is actually a name for a group of muscular dystrophies, all of which weaken the muscles of the hip and shoulder girdles. Some forms are more severe than others, with involvement of muscle groups varying among people with the disorder. This clinical trial will target the types of LGMD that result from an absence or abnormality in any of four closely related muscle proteins known as alpha-, beta-, gamma- and delta-sarcoglycans.

In some forms of LGMD, one of the four sarcoglycan proteins normally found in the muscle cell membrane is missing or nonfunctional (gray). The result is that some neighboring proteins (gray) become lost and the membrane is disrupted, causing muscle cell damage and muscle weakness. By injecting a working gene into a foot muscle, MDA researchers hope to restore a cluster of proteins that normally protects the muscle membrane.

"We're not looking for improved strength or any improvement in function at this time," said James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania and coordinator of the trial. "This is what we call a 'proof-of-principle' study, in which we're testing whether an approach that has worked in animals can, in fact, be safely transferred to humans."

HOW WE GOT HERE

The LGMD trial, although simple in principle, has been complex in its development. It's the brainchild of MDA's Task Force on Gene Therapy, chaired by Wilson and comprising researchers and physicians at several institutions. Members of this group from the University of Pennsylvania; Ohio State; the University of Iowa in Iowa City; Boston Children's Hospital; Washington University in St. Louis; Vanderbilt University in Nashville, Tenn.; and the University of Rochester (N.Y.) have established a registry of people with sarcoglycan-deficient LGMD. People from this group will be chosen to participate in the current and future trials. More than a dozen such people have been identified so far.

Among the many MDA-supported researchers whose work has been essential to the effort are: Kevin Campbell of the University of Iowa, the key player in identifying several sarcoglycan genes and the proteins that are made from the genes (he'll be analyzing muscle samples for the current LGMD trial); Elizabeth McNally of the University of Chicago, whose work with the gamma-sarcoglycan gene showed its association with LGMD; Hansell Stedman of the University of Pennsylvania, whose work in gene delivery systems has been innovative and promising; and Mendell, MDA clinic director at Ohio State, a muscular dystrophy specialist and an experienced trial coordinator.

"The work of many scientists and clinicians has brought us to this point in our fight against muscular dystrophy," Mendell said, "but the dedication of our patients has also played a critical role and can never be underestimated, underappreciated or taken for granted."

WHO ARE THE PARTICIPANTS?

One person with sarcoglycan-deficient LGMD at a time will receive a gene therapy injection; if all goes well with the first injection, a total of six to 12 people will receive injections at intervals of several weeks. Prospective participants will be drawn from the initial screening process and will be carefully evaluated according to a number of criteria. If you're interested in participating in this or a later phase of the trial, see the "MDA Gene Therapy Clinical Trials" page on MDA's Web site (under Research -- Active Clinical Trials). You may also apply by calling MDA at (800) 572-1717.

WHAT'S GOING TO HAPPEN?

The goal of the trial is to evaluate the safety of a sarcoglycan gene that has been inserted into a virus known as AAV (adeno-associated virus) and delivered by intramuscular injection to a small muscle in the foot.

The AAV has been highly modified so that it can no longer duplicate itself in the body and cause an immune system rejection.

Each participant will receive about 1 fluid ounce of the gene therapy vector carrying the sarcoglycan gene in a muscle on the outside edge of the top of the foot; in the same muscle in the other foot, they'll each receive an injection of saline (salt solution). Neither the investigators nor the participants will know which foot muscle got the saline and which got the gene therapy vector.

The researchers will check carefully for any sign of inflammation or fever for three or four days, during which participants will stay in the hospital at Ohio State University. The researchers want to see not only whether the patients have any adverse reactions to the injections, but also whether there is evidence of viral replication in their bodies (the modified virus used for this trial shouldn't make copies of itself the way a natural virus would).

Seven weeks after the injections, participants will have muscle biopsies done in both feet to see the effects, if any, of the gene transfer.

WHAT WILL WE LEARN?

What we won't learn in this trial is whether gene therapy improves strength or function in human muscular dystrophy, the researchers emphasize. However, we'll learn a lot about the feasibility of doing gene therapy in humans.

The researchers expect to learn whether the AAV vector will deliver the sarcoglycan gene to muscle cells; whether the gene, once delivered to the cells, will lead to production of a sarcoglycan protein, and how long such production will last; whether there will be a significant immune response that could interfere with the gene therapy or cause damage to any body tissues; and whether the virus could regain the ability to multiply in the body.

WHAT DOES THE FUTURE HOLD?

Much will depend on the outcome of this preliminary safety trial. If all goes well, the next steps will involve "scale-up" -- delivering the gene therapy vector to more muscle cells in more people in phase 2 and phase 3 trials. These later trials will test muscle strength, in addition to continuing to monitor safety issues. Eventually, other forms of muscular dystrophy and other neuromuscular disorders will be targeted.

"We're a long way from curing muscular dystrophy," Mendell said, "but I'm hopeful, as are many of my colleagues, that this first step in gene therapy will mark the beginning of a new era."

MDA remains dedicated to finding treatments and cures for all of the 40 neuromuscular disorders in its program. Currently, researchers supported by MDA are studying the problem of gene therapy for Duchenne and Becker muscular dystrophies (see "Overcoming Hurdles in Gene Therapy for DMD"), amyotrophic lateral sclerosis, congenital muscular dystrophies, myotubular myopathy, acid maltase deficiency, phosphorylase deficiency, mitochondrial disorders and others.