Utrophin Gene Therapy Benefits DMD Mice

Injecting genes for the muscle protein utrophin may be a viable strategy to pursue for treating Duchenne muscular dystrophy (DMD), say researchers at McGill University in Montreal.

MDA grantees George Karpati, Basil Petrof and Josephine Nalbantoglu were part of a team that injected genes for utrophin into the leg muscles of mice missing the closely related dystrophin protein. These dystrophin-deficient mice have a disease resembling human DMD.

The advantage to injecting utrophin instead of dystrophin genes is that the immune systems of at least some children and adolescents may reject the new dystrophin as a foreign protein, while they will almost certainly accept extra utrophin, since people with DMD already make utrophin.

Newborn and adult mice showed evidence of utrophin production in the injected muscles, as well as better resistance to contraction-related damage and, in some cases, better force generation than on the uninjected side of the body. However, in both groups, the beneficial effects diminished over the course of a few months to a year after injection.

“A critical issue is to determine the minimum amount of utrophin that is sufficient to successfully pinch-hit for dystrophin,” Karpati said, noting that utrophin is normally found in muscle fibers only at the place where they intersect with nerve fibers (the synapse) and that utrophin throughout the fiber membrane will be necessary to successfully treat DMD.

The other problem that must be solved is “the substantial decline of the amount of extrasynaptic [outside the synapse] utrophin over time,” Karpati added. He said it does not appear to be a problem of immune system rejection.

The authors, who published their results online July 31 in Molecular Therapy, say that utrophin therapy might be optimized by combining utrophin gene transfer with a compound that increases protein production from the patient’s own utrophin genes.

MDA is supporting research on the latter strategy (see “ID of Utrophin Brake”), as well as a clinical trial to test the effects of a muscle injection of dystrophin genes into boys with DMD.