Exon skipping peptide-conjugated morpholinos downregulate dynamin 2 to rescue centronuclear myopathy.

ABSTRACT: Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and disorganization of myofibres. These conditions can result from dominant mutations in the DNM2 gene encoding the GTPase dynamin, making them potential targets for antisense therapy. Preclinical studies suggested decreasing DNM2 as a therapy but a recent clinical trial with antisense oligonucleotides did not effectively address the disease and showed some non-muscle toxicity. Here, to promote DNM2 downregulation in muscle versus other tissues, we used an exon skipping peptide-conjugated phosphorodiamidate morpholino (PPMO) targeting Dnm2 exon 6 splicing in the Dnm2R369W/+ mouse model for the moderate CNM form. Intravenous administration of PPMOs at an early age (4 weeks) significantly downregula

SUBMITTER: Moschovaki-Filippidou F 

PROVIDER: S-EPMC12677909 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature