Peptide-conjugated antimiRs improve myotonic dystrophy type 1 phenotypes by promoting endogenous MBNL1 expression
© 2023 The Authors..
Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the DMPK gene that generates toxic RNA with a myriad of downstream alterations in RNA metabolism. A key consequence is the sequestration of alternative splicing regulatory proteins MBNL1/2 by expanded transcripts in the affected tissues. MBNL1/2 depletion interferes with a developmental alternative splicing switch that causes the expression of fetal isoforms in adults. Boosting the endogenous expression of MBNL proteins by inhibiting the natural translational repressors miR-23b and miR-218 has previously been shown to be a promising therapeutic approach. We designed antimiRs against both miRNAs with a phosphorodiamidate morpholino oligonucleotide (PMO) chemistry conjugated to cell-penetrating peptides (CPPs) to improve delivery to affected tissues. In DM1 cells, CPP-PMOs significantly increased MBNL1 levels. In some candidates, this was achieved using concentrations less than two orders of magnitude below the median toxic concentration, with up to 5.38-fold better therapeutic window than previous antagomiRs. In HSALR mice, intravenous injections of CPP-PMOs improve molecular, histopathological, and functional phenotypes, without signs of toxicity. Our findings place CPP-PMOs as promising antimiR candidates to overcome the treatment delivery challenge in DM1 therapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:34 |
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| Enthalten in: |
Molecular therapy. Nucleic acids - 34(2023) vom: 12. Dez., Seite 102024 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
González-Martínez, Irene [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 26.09.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.omtn.2023.09.001 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362406383 |
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| 100 | 1 | |a González-Martínez, Irene |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Peptide-conjugated antimiRs improve myotonic dystrophy type 1 phenotypes by promoting endogenous MBNL1 expression |
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| 520 | |a © 2023 The Authors. | ||
| 520 | |a Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the DMPK gene that generates toxic RNA with a myriad of downstream alterations in RNA metabolism. A key consequence is the sequestration of alternative splicing regulatory proteins MBNL1/2 by expanded transcripts in the affected tissues. MBNL1/2 depletion interferes with a developmental alternative splicing switch that causes the expression of fetal isoforms in adults. Boosting the endogenous expression of MBNL proteins by inhibiting the natural translational repressors miR-23b and miR-218 has previously been shown to be a promising therapeutic approach. We designed antimiRs against both miRNAs with a phosphorodiamidate morpholino oligonucleotide (PMO) chemistry conjugated to cell-penetrating peptides (CPPs) to improve delivery to affected tissues. In DM1 cells, CPP-PMOs significantly increased MBNL1 levels. In some candidates, this was achieved using concentrations less than two orders of magnitude below the median toxic concentration, with up to 5.38-fold better therapeutic window than previous antagomiRs. In HSALR mice, intravenous injections of CPP-PMOs improve molecular, histopathological, and functional phenotypes, without signs of toxicity. Our findings place CPP-PMOs as promising antimiR candidates to overcome the treatment delivery challenge in DM1 therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a MBNL proteins | |
| 650 | 4 | |a MT: Oligonucleotides: Therapies and Applications | |
| 650 | 4 | |a PMO chemistry | |
| 650 | 4 | |a alternative splicing | |
| 650 | 4 | |a antisense oligonucleotides | |
| 650 | 4 | |a biodistribution | |
| 650 | 4 | |a cell-penetrating peptides | |
| 650 | 4 | |a microRNAs | |
| 650 | 4 | |a muscle dysfunction | |
| 650 | 4 | |a myotonic dystrophy | |
| 700 | 1 | |a Cerro-Herreros, Estefanía |e verfasserin |4 aut | |
| 700 | 1 | |a Moreno, Nerea |e verfasserin |4 aut | |
| 700 | 1 | |a García-Rey, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Espinosa-Espinosa, Jorge |e verfasserin |4 aut | |
| 700 | 1 | |a Carrascosa-Sàez, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Piqueras-Losilla, Diego |e verfasserin |4 aut | |
| 700 | 1 | |a Arzumanov, Andrey |e verfasserin |4 aut | |
| 700 | 1 | |a Seoane-Miraz, David |e verfasserin |4 aut | |
| 700 | 1 | |a Jad, Yahya |e verfasserin |4 aut | |
| 700 | 1 | |a Raz, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Wood, Matthew J |e verfasserin |4 aut | |
| 700 | 1 | |a Varela, Miguel A |e verfasserin |4 aut | |
| 700 | 1 | |a Llamusí, Beatriz |e verfasserin |4 aut | |
| 700 | 1 | |a Artero, Rubén |e verfasserin |4 aut | |
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