One therapeutic approach for Duchenne muscular dystrophy (DMD) involves increasing the expression of utrophin to compensate for the absence of dystrophin, with which it shares a high degree of homology.
A team at Généthon used the CRISPR-Cas9 system to generate insertions or deletions at the binding site of the Let-7c microRNA in order to lift the repression of utrophin expression.
- When tested on a 3D model of human DMD muscles, this genome-editing strategy led to increased utrophin expression and muscle contraction strength, as well as improved calcium regulation.
- In mdx mice, a model of the disease, a single intramuscular or intravenous administration via AAV9 vectors led to utrophin overexpression in certain muscles (increased by a factor of 1.3 and 2, respectively, in the diaphragm and tibialis anterior, for example) and to an improvement in several histological and functional characteristics, such as a reduction in fibrosis.
- The benefits remain modest, suggesting that disruption of a single microRNA binding site cannot fully derepress utrophin and that combinatorial strategies targeting multiple sites may be necessary for a more robust effect.
This approach has an encouraging safety profile and is potentially applicable to all patients, regardless of their genotype.
