Exon skipping converts an out-of-frame mutation into an in-frame mutation leading to an internally deleted but partially functional dystrophin.

This therapeutic approach has demonstrated considerable success using antisense oligonucleotides (AONs), particularly in recent clinical studies. AONs have the enormous advantage of not producing an immune response, but have the disadvantage of having to be regularly injected to maintain therapeutic benefit.

The French group based at the Institute of Myology, one of the leading international centres,have shown that the antisense sequences could be disguised in a small nuclear RNA such as U7snRNA or U1snRNA.

These therapeutic molecules are packaged in adeno-associated viral vectors (AAV), which ensure a permanent production therapeutic antisense in mouse and dog models. A one-shot treatment of AAV-U7 in animal models has been shown to restore some dystrophin expression, which is associated with an improvement in muscle force.

Because most young people living with Duchenne are treated with corticosteroids which might have an effect on therapeutic AAV treatment, the group propose to evaluate benefits of a combined treatment of therapeutic AAVs and corticosteroids in mdx mouse model of DMD (i) to investigate whether increase of muscle strength and better muscle environment state by corticosteroid treatment would slow down the loss of AAV vectors, and (ii) to characterize the corticosteroid mechanism of action and their impact on the muscle machinery.

Stéphanie Lorain, lead investigator from the Institute of Myology said:

“With the first clinical trial planned with this technology to deliver exon skipping planned later this year, this project will give us a better understanding of the potential treatment effect with best standards of care. We are pleased that Action Duchenne are supporting this important project.”