Muscle function recovery in golden retriever muscular dystrophy after AAV1-U7 exon skipping

French investigators have demonstrated that antisense oligos delivered with a gene therapy approach can improve muscle function and structure over the short term in dogs that lack dystrophin, according to a new article in the journal Molecular Therapy by Dr. Luis Garcia and colleagues from the Institute de Myologie in Paris.

Although the procedure, which caused exons 7 and 8 to be skipped in dogs to restore the dystrophin reading frame, led to some functional improvements, it did not fully correct the muscle weakness and the vector could no longer be identified in the muscle at a five year follow-up. The authors suggest that the form of dystrophin produced by skipping exons 7 and 8 may not be fully functional since it would be predicted to lack the “actin binding domain” which anchors the dystrophin protein to the inside of the muscle fiber. If the dystrophin lacking exons 7 and 8 is not fully functional, then eventually those fibers carrying it may die, which would explain why the vector was lost by five years after the procedure.

They conclude that this gene therapy approach to exon skipping may only be useful for those with Duchenne whose exons can be skipped to produce a highly functional form of dystrophin. Presumably the less functional forms of dystrophin produced by exon skipping may still be helpful if they are delivered regularly as antisense oligos intravenously or by injection as in the ongoing studies of Sarepta, GSK and Prosensa.

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