Spotlight on Research for 2006

September 2006 (historical)

Gene Therapy for Congenital Muscular Dystrophies Successful in Mouse Model

Scientists funded in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases have delivered a gene by viral vector that blocks muscle degeneration and restores its function in mice with congenital muscular dystrophies (CMD).

In humans, CMD is characterized by severe muscle weakness in infancy, often leading to death before age 5. Although this gene therapy approach does not completely reverse muscle wasting in the mouse model, it may have the potential to extend the otherwise very short lives of children born with this disease.

People with CMD are missing a protein known as laminin-alpha2, which is normally found in the basal lamina, the layer of cells that surrounds muscle fibers and other cells and maintains the structural integrity of muscle tissue. The absence of this protein is what keeps the basal lamina from maintaining the structural integrity of muscle tissue. Agrin, another component of the basal lamina, could compensate for the absence of laminin-alpha2 and restore basal lamina integrity, but normal expression of agrin is too low to correct for the lack of laminin-alpha2.

Xiao Xiao, Ph.D., and his colleagues at the University of Pittsburgh School of Medicine sought a way to strengthen the basal lamina. They were aware that a previous mouse model lacking laminin-alpha2 had been engineered to overexpress a miniature form of agrin (miniagrin). This miniagrin corrected many of the CMD-like problems. Dr. Xiao's group developed a vector to deliver the miniagrin gene to affected muscle. The vector uses adeno-associated virus (AAV), which is known to efficiently penetrate muscle tissue.

When researchers treated CMD mice with the miniagrin gene using the AAV delivery system, the growth rate, locomotive activity and lifespan of the mice significantly exceeded those of their untreated littermates:

  • At age six weeks, the average body weight of the treated mice was 80 percent greater than that of their untreated counterparts.
  • The treated mice were more physically active than the untreated ones, and they showed much better locomotor function.
  • The 50 percent survival time for the treated mice was more than 17 weeks, while for untreated mice it was just 4 weeks.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHD), all part of the National Institutes of Health, provide funding to six centers that study muscular dystrophy. Known as the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers, they are housed at academic institutions and hospitals around the country. The University of Pittsburgh is home to one of these centers.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at

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Qiao C, et al. Amelioration of laminin-alpha2-deficient congenital muscular dystrophy by somatic gene transfer of miniagrin. PNAS 2005;102(34);11999-12004.