Benefits of therapy by dynamin-2-mutant-specific silencing are maintained with time in a mouse model of dominant centronuclear myopathy

• Main Authors: Delphine Trochet (Author), Bernard Prudhon (Author), Lylia Mekzine (Author), Mégane Lemaitre (Author), Maud Beuvin (Author), Laura Julien (Author), Sofia Benkhelifa-Ziyyat (Author), Mai Thao Bui (Author), Norma Romero (Author), Marc Bitoun (Author)
• Format: Book
• Published: Elsevier, 2022-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Dominant dynamin 2 (DNM2) mutations are responsible for the autosomal dominant centronuclear myopathy (AD-CNM), a rare progressive neuromuscular disorder ranging from severe neonatal to mild adult forms. We previously demonstrated that mutant-specific RNA interference is an efficient therapeutic strategy to rescue the muscle phenotype at the onset of the symptoms in the AD-CNM knockin-Dnm2R465W/+ mouse model. Our objective was to evaluate the long-term benefit of the treatment along with the disease time course. We demonstrate here that the complete rescue of the muscle phenotype is maintained for at least 1 year after a single injection of adeno-associated virus expressing the mutant-specific short hairpin RNA (shRNA). This was achieved by a maintained reduction of the mutant Dnm2 transcript. Moreover, this long-term study uncovers a pathological accumulation of DNM2 protein occurring with age in the mouse model and prevented by the treatment. Conversely, a physiological DNM2 protein decrease with age was observed in muscles from wild-type mice. Therefore, this study highlights a new potential pathophysiological mechanism linked to mutant protein accumulation and underlines the importance of DNM2 protein expression level for proper muscle function. Overall, these results strengthen the allele-specific silencing approach as a robust, safe, and efficient therapy for AD-CNM.

Item Description

2162-2531
10.1016/j.omtn.2022.02.009