Gene Therapy Trial in MD first to show promise beyond safety

TUCSON, Ariz., April 15, 2009 — Researchers supported by the Muscular Dystrophy Association (MDA) and the National Institutes of Health say results of a gene therapy trial in three people with limb-girdle muscular dystrophy (LGMD) are the first to show promise beyond safety alone, MDA announced today.

"These exciting results demonstrate the feasibility of gene therapy to treat limb-girdle muscular dystrophy," said Jane Larkendale, portfolio director with MDA Venture Philanthropy, a program that moves basic research into treatment development. "The lack of adverse events seen in this trial not only supports gene therapy for this disease, but it also supports such therapies for many other diseases."

Neurologist Jerry Mendell, co-director of the MDA clinic and director of the Center for Gene Therapy at Nationwide Children's Hospital in Columbus, Ohio, received MDA support to coordinate the study team, which announced its results online today in Annals of Neurology.

Although the primary goal of the small trial was to establish the safety of intramuscular injection of the alpha-sarcoglycan gene into a foot muscle, the investigators also evaluated how long gene activity persisted in the muscle, the level of protein produced from the gene and the response of the immune system to the gene.

No adverse events, such as rejection of the therapy by the immune system, occurred during the trial, reassuring researchers of the likelihood that their approach is safe in people with the alpha-sarcoglycan-deficient form of LGMD, a form of muscular dystrophy affecting children and adults that begins with weakness in the muscles surrounding the shoulders and hips.

Moreover, all three trial participants produced four to five times the amount of alpha-sarcoglycan protein in the gene-injected foot muscle compared to the amount in the corresponding muscle on the other foot, which received a salt solution. This level of output from the transferred gene persisted until at least the date of the last evaluation, which was six weeks after injection in one patient, seven weeks in another, and 12 weeks in the third.

In each case, the alpha-sarcoglycan protein assumed its normal position in the membrane of the muscle fiber and restored the structure of a protein cluster that's normally found at that location but is missing in muscles that lack alpha-sarcoglycan. The cluster is crucial to the integrity of the muscle fibers.

The response of the immune system to the transferred gene and its carrier, a viral shell, was brief and minimal in all cases and did not interfere with gene activity.

No improvement in function was expected from this direct injection into a very small area. A delivery method that reaches a large muscle area will be necessary to improve function, the researchers say.

"In summary," the researchers note, "this is the first gene therapy trial in muscular dystrophy demonstrating promising findings, setting the stage for moving forward with treatment of this catastrophic group of diseases. ... Nevertheless, clinically meaningful outcomes will require vascular [into blood vessels] delivery to multiple muscle groups."

They also note that the study has potential relevance for other muscle diseases and for diseases in which muscle tissue can be used to secrete therapeutic proteins into the bloodstream.

About Limb-Girdle MD

LGMD is one of nine types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles. A mutation (flaw) in any of at least 15 genes that affect various muscle proteins can cause the disease. Alpha-sarcoglycan is one of these proteins. When alpha-sarcoglycan is lacking, muscles develop weakness and wasting, starting in the shoulder and hip area and spreading to other muscle groups. Loss of walking ability can occur. Alpha-sarcoglycan-deficient LGMD is inherited in a recessive pattern, meaning a child needs to inherit a mutation in an alpha-sarcoglycan gene from each parent to show symptoms.

About This Study

The study participants, who were ages 12, 13 and 14, all have alpha-sarcoglycan-deficient LGMD and have lost the ability to walk.

They each received an injection of alpha-sarcoglycan genes encased in carriers made from altered type 1 adeno-associated viruses.

Each gene was coupled with a molecular "on switch" called a promoter. The researchers used a promoter known as MCK, which works only in muscle tissue, avoiding unwanted protein production elsewhere in the body.

One foot muscle received the genes, and the corresponding muscle on the other foot received saline alone. Neither the investigators nor the trial participants knew which injection contained the gene until after muscle biopsy results were evaluated several weeks later.

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