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

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 str...

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Detalles Bibliográficos
Autores principales: Trochet, Delphine, Prudhon, Bernard, Mekzine, Lylia, Lemaitre, Mégane, Beuvin, Maud, Julien, Laura, Benkhelifa-Ziyyat, Sofia, Bui, Mai Thao, Romero, Norma, Bitoun, Marc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8889367/
https://www.ncbi.nlm.nih.gov/pubmed/35282416
http://dx.doi.org/10.1016/j.omtn.2022.02.009
Descripción
Sumario: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-Dnm2(R465W/+) 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.