Novel Gene Therapy Treatment Extends Life of Mice Severely Affected by Muscular Dystrophy

An alternative gene therapy approach was used to successfully treat a mouse model of Duchenne muscular dystrophy (DMD).

DMD is caused by mutations in the gene that encodes the protein dystrophin and the subsequent disruption of the dystrophin-associated protein complex (DAPC). The disease effects about one of every 3,500 boys whose muscle function is so degraded that they die usually before they reach the age of 30.


To develop methods for treating this syndrome, investigators at Ohio State University (Columbus, USA) chose to work with mice deficient for dystrophin and utrophin, (mdx/utrn−/−) that die between six and 20 weeks of age because of severe muscle weakness, pronounced growth retardation, and kyphosis rather than the more frequently used dmx model whose animals are clinically normal despite lacking dystrophin.

Dystrophin deficiency has been definitively established as one of the root causes of the general class of myopathies collectively referred to as muscular dystrophy. In normal muscle cells, utrophin is located at the neuromuscular synapse and myotendinous junctions. It is necessary for normal membrane maintenance, and for the clustering of the acetylcholine receptor.

The investigators evaluated an alternative to dystrophin replacement by overexpressing the ITGA7 (integrin, alpha 7) gene using adeno-associated virus (AAV) delivery. ITGA7 is a laminin receptor in skeletal muscle that, like the dystrophin–glycoprotein complex, links the extracellular matrix to the internal actin cytoskeleton. ITGA7 is expressed in DMD patients and its overexpression does not elicit an immune response.

In the current study, five to seven day-old mice deficient for dystrophin and utrophin, (mdx/utrn−/−)were treated with the ITGA7 gene delivered via the AAV carrier. Results published in the August 11, 2015, online edition of the journal Human Gene Therapy revealed that by eight weeks following ITGA7 injection, there was widespread expression of the gene at the sarcolemma of multiple muscles. The increased expression of ITGA7 significantly extended longevity and reduced common features of the mdx/utrn−/− mouse, including kyphosis. Overexpression of alpha7 expression protected against loss of force following contraction-induced damage, and increased specific force in the diaphragm and EDL (extensor digitorum longus) muscles eight weeks after gene transfer.

Mice of the mdx/utrn−/− line usually die between six to 20 weeks of age, but gene transfer of alpha7 extended longevity by more than 10 weeks.

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Ohio State University