Systemic Delivery of Peptide-Conjugated Antisense Oligonucleotides Leads to Long-Lasting Correction of Myotonic Dystrophy Type I

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Klein, Arnaud F. | Varela, Miguel A. | Arandel, Ludovic | Holland, Ashling | Naouar, Naira | Arzumanov, Andrey | Ferry, Arnaud | Bassez, Guillaume | Wood, Matthew J. | Furling, Denis

Edité par CCSD -

International audience. Antisense oligonucleotides (ASOs) targeting pathologic RNAs have shown promising therapeutic corrections for myotonic dystrophy type 1 (DM1), abolishing the toxic RNA gain-of-function mechanism caused by nuclear-retained mutant transcripts containing CUG expansions (CUGexp). However, systemic use of ASOs for DM1 remains challenging due to poor drug distribution into skeletal muscle. Here we show that Pip6a-conjugated morpholino phosphorodiamidate oligomer (PMO) dramatically enhanced ASO delivery into striated muscles of HSA-LR mice following systemic administration in comparison to unconjugated PMO. Pip6a-PMOs targeting pathologic expansions reverse the detrimental sequestration of MBNL1 splicing factor by nuclear CUGexp-RNA foci and consequently MBNL1 functional loss that is responsible for splicing defects and muscle dysfunction. Thus, we demonstrate that Pip6a-PMO induces high efficacy, long-lasting correction of DM1-associated phenotypes at both molecular and functional levels, including in patient derived muscle cells with long repeats, strongly supporting the use of advanced peptide-conjugates for systemic corrective therapy in DM1.

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