11 research outputs found

    Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice

    No full text
    Antisense oligonucleotides (ASOs) targeting pathologic RNAs have shown promising therapeutic corrections for many genetic diseases including myotonic dystrophy (DM1). Thus, ASO strategies for DM1 can abolish the toxic RNA gain-of-function mechanism caused by nuclear-retained mutant transcripts containing CUG expansions (CUGexp). However, systemic use of ASOs for this muscular disease remains challenging due to poor drug distribution to skeletal muscle. To overcome this limitation, we test an arginine-rich Pip6a cell-penetrating peptide and show that Pip6a-conjugated morpholino phosphorodiamidate oligomer (PMO) dramatically enhanced ASO delivery into striated muscles of DM1 mice following systemic administration in comparison with unconjugated PMO and other ASO strategies. Thus, low-dose treatment of Pip6a-PMO-CAG targeting pathologic expansions is sufficient to reverse both splicing defects and myotonia in DM1 mice and normalizes the overall disease transcriptome. Moreover, treated DM1 patient-derived muscle cells showed that Pip6a-PMO-CAG specifically targets mutant CUGexp-DMPK transcripts to abrogate the detrimental sequestration of MBNL1 splicing factor by nuclear RNA foci and consequently MBNL1 functional loss, responsible for splicing defects and muscle dysfunction. Our results demonstrate that Pip6a-PMO-CAG induces high efficacy and long-lasting correction of DM1-associated phenotypes at both molecular and functional levels, and strongly support the use of advanced peptide-conjugates for systemic corrective therapy in DM1

    Children using Day Nurseries’ Facilities can be Associated with more Risk to Nonnutritive Sucking Habits

    No full text

    Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

    No full text

    Pathogen-Inaktivierungssysteme fĂĽr Thrombozytenkonzentrate

    No full text

    Molecular Therapies for Muscular Dystrophies

    No full text
    corecore