Treatment In Mice Proves Effective Against Duchenne Muscular Dystrophy

By enhancing the production of a naturally occurring molecule on muscle tissue, the scientists reduced muscle-related problems and increased by three-fold the lifetimes of affected mice. Their work appears in the March 19 issue of the Journal of Cell Biology.

The work suggests that a gene therapy or a pharmaceutical approach targeting the molecule may be possible for human treatment, said Stephen J. Kaufman, a professor of cell and structural biology and of the College of Medicine. "The implications are that you could do gene therapy with an integrin chain to treat a muscular dystrophy that’s caused by a membrane protein deficiency," he said. "Or you could chemically stimulate integrin chain production from the patient’s existing integrin chain genes."

Kaufman’s lab discovered the molecule in question – the alpha 7 integrin – in 1985. A deficiency of this molecule exists in several forms of congenital muscular dystrophy. Conversely, Kaufman and his colleagues found that more of the integrin is present in Duchenne patients. These patients fail to produce another protein, dystrophin, which muscles also require for structural and functional integrity.

This discovery led to the idea that excess integrin may compensate for the lack of dystrophin and another similar protein, utrophin. To test their hypothesis, Kaufman’s team used mice that did not produce dystrophin or utrophin, and they engineered them to produce even more of the alpha 7 integrin protein. Untreated mice developed debilitating muscular dystrophy, suffered severe weight loss and 50 percent died before reaching 12 weeks of age. Mice with enhanced alpha integrin production did not suffer severe muscular problems, maintained good mobility and lived to an average age of 38 weeks.

Duchenne muscular dystrophy, caused by a recessive genetic defect, affects one in 3,300 males. The disease usually begins in early childhood and often is fatal by age 30. It is the most prevalent of the muscular dystrophy family of neuromuscular diseases. Patients with Becker, limb girdle and other muscular dystrophies also might benefit from the approach used in the study, Kaufman said.

"The potential exists to enhance the expression of the endogenous normal alpha 7 integrin gene, or extend the lifetime of the alpha 7 protein," he said. "This would even avoid the need for what we think of as classical gene therapy."

Co-authors with Kaufman on the study were departmental colleague Dean J. Burkin, graduate student Gregory Q. Wallace and former graduate student Kimberly J. Nicol, all of the UI, and David J. Kaufman of the National Cancer Institute in Bethesda, Md. The Muscular Dystrophy Association and National Institutes of Health supported the research.