Dominant mutations in the DNM2 gene encoding Dynamin 2 (DNM2) cause centronuclear dominant myopathy (CNM), rare cases of Charcot-Marie-Tooth disease and hereditary spastic paraplegia. Deleterious overexpression of DNM2 has also been found in several other diseases.
In February 2018*, researchers from the Institute of Myology led by Marc Bitoun** had published the proof of concept of an allele-specific RNA interference therapy, aiming to silence the mutated mRNA without affecting the normal allele, in a mouse model and in patient-derived cells, both expressing the DNM2 mutation most frequent in CNM. In May 2022***, the team demonstrated the long-term therapeutic efficacy of this gene therapy mutation silencing approach. Indeed, after a single injection of AAV in 1-month-old mice, the restoration of the muscle phenotype was still observed 1 year later.
In this article published in August 2022****, the researchers report that they have developed versatile interfering RNAs (siRNAs) that can be used regardless of the mutation. They have shown the beneficial effects of these siRNAs for a range of defects occurring in patient-derived cell lines.
These data suggest that a few siRNAs can target the vast majority of patients with mutations or overexpression of DNM2.
** Leader of the team Muscle Organization & Therapy of Dominant Centronuclear Myopathy, Myology Centre for Research at the Institute of Myology.
