Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice.
Fiche publication
Date publication
juin 2017
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Mme MESSADDEQ Nadia
Tous les auteurs :
Tasfaout H, Buono S, Guo S, Kretz C, Messaddeq N, Booten S, Greenlee S, Monia BP, Cowling BS, Laporte J
Lien Pubmed
Résumé
Centronuclear myopathies (CNM) are non-dystrophic muscle diseases for which no effective therapy is currently available. The most severe form, X-linked CNM, is caused by myotubularin 1 (MTM1) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (DNM2) mutations. We previously showed that genetic reduction of DNM2 expression in Mtm1 knockout (Mtm1KO) mice prevents development of muscle pathology. Here we show that systemic delivery of Dnm2 antisense oligonucleotides (ASOs) into Mtm1KO mice efficiently reduces DNM2 protein level in muscle and prevents the myopathy from developing. Moreover, systemic ASO injection into severely affected mice leads to reversal of muscle pathology within 2 weeks. Thus, ASO-mediated DNM2 knockdown can efficiently correct muscle defects due to loss of MTM1, providing an attractive therapeutic strategy for this disease.
Mots clés
Animals, Disease Models, Animal, Dynamin II, genetics, Female, Kidney, metabolism, Liver, metabolism, Male, Mice, Mice, Knockout, Muscle Contraction, Muscle, Skeletal, metabolism, Mutation, Myopathies, Structural, Congenital, genetics, Oligonucleotides, Antisense, genetics, Phenotype, Protein Tyrosine Phosphatases, Non-Receptor, genetics, Recombination, Genetic
Référence
Nat Commun. 2017 Jun 7;8:15661