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Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice
Arnaud F. Klein, … , Denis Furling, Matthew J.A. Wood
Arnaud F. Klein, … , Denis Furling, Matthew J.A. Wood
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(11):4739-4744. https://doi.org/10.1172/JCI128205.
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Concise Communication

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

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Abstract

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 nucleus-retained mutant DMPK (DM1 protein kinase) transcripts containing CUG expansions (CUGexps). 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 with 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 long-lasting correction with high efficacy 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.

Authors

Arnaud F. Klein, Miguel A. Varela, Ludovic Arandel, Ashling Holland, Naira Naouar, Andrey Arzumanov, David Seoane, Lucile Revillod, Guillaume Bassez, Arnaud Ferry, Dominic Jauvin, Genevieve Gourdon, Jack Puymirat, Michael J. Gait, Denis Furling, Matthew J.A. Wood

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Figure 4

Pip6a-PMO corrects DM1-specific molecular symptoms in DM1 muscle cells.

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Pip6a-PMO corrects DM1-specific molecular symptoms in DM1 muscle cells.
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Four-day-differentiated immortalized DM1 myoblasts (2600 CTG repeats) were treated with 1 μM Pip6a-PMO and analyzed after 24 hours. (A) Combined FISH (Cy3-CAG, red) and immunofluorescence (MBNL1, green) on DM1 or WT differentiated myoblasts. Scale bars: 10 μm. (B) Quantification of splicing corrections by RT-PCR (WT n = 4; DM1 and Pip6a-PMO n = 7). (C) Quantification of mean number of foci per nucleus in treated DM1 differentiated myoblasts (n = 4; >500 nuclei per n). (D) Quantification of the number of nuclei without foci in treated DM1 differentiated myoblasts (n = 4; >500 nuclei per n). (E and F) Levels of mutant DMPK and normal DMPK transcripts analyzed by Northern blot using a DMPK probe (n = 4). Data are expressed as mean ± SEM. ***P < 0.001; ****P < 0.0001 by 1-way ANOVA with Newman-Keuls post hoc test (B and F) or Mann-Whitney test (C and D). NS, not significant.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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