Spotlight on Research 2008

February 2008 (historical)

Gene Transfer Successful in Mouse Model of Limb-Girdle Muscular Dystrophy

Scientists have found that progression of limb-girdle muscular dystrophy type 2D (LGMD-2D) can be prevented over the long term in mice after transferring a correctly functioning form of the alpha-sarcoglycan gene (SGCA) to their muscle tissue. The research was partly supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

The LGMDs are a group of genetic and degenerative disorders in which the muscle fiber membrane breaks down, causing progressive muscle weakness. One type, LGMD-2D, is caused by mutations in the SGCA gene. Scientists used knockout (alpha-sarcoglycan-deficient) mice to test whether the transfer of the normal human SGCA gene would provide long-term protection from muscle degeneration.

Currently, there are no effective treatments for LGMD. Kevin Campbell, Ph.D., at the University of Iowa , and his colleagues at the University of Florida College of Medicine theorized that, because LGMD-2D is caused by a single gene defect, it may be possible to treat this disorder with gene therapy. Exploring this approach requires an effective gene delivery technique and methods for assessing whether the gene transfer is working.

The investigators used a modified version of an adeno-associated virus as a vector to deliver the gene. This type of vector performs well when genes are transferred into muscles. The investigators also used magnetic resonance imaging to assess the usefulness of the gene transfer. The scientists found that the SGCA gene transfer and subsequent SGCA gene expression prevented muscle tissue damage. This was confirmed by an analysis of muscle samples, which showed decreased Evan's blue dye accumulation among samples in which the gene transfer had taken place. Evan's blue dye accumulates in areas in the muscle where muscle fiber membrane breakdown has occurred.

The researchers analyzed resistance to passive stretch in hind leg muscles of young and older mice as another measure of gene-transfer efficacy. They found that the animals that had received the gene transfer showed long-term resistance to stretch that was comparable to normal mice. Untreated animals, however, showed either low resistance, due to broken muscle fiber membrane, or high resistance, due to the formation of fibrous lesions.

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Pacak, C, et al. Long-term Skeletal Muscle Protection After Gene Transfer in a Mouse Model of L`1GMD-2D. Molecular Therapy . 2007;15(10);1775-1781.