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MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice

Antisense oligonucleotide (AO)‐mediated exon‐skipping therapies show promise in Duchenne muscular dystrophy (DMD), a devastating muscular disease caused by frame‐disrupting mutations in the DMD gene. However, insufficient systemic delivery remains a hurdle to clinical deployment. Here, we demonstrat...

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Autores principales: Ran, Ning, Lin, Caorui, Leng, Ling, Han, Gang, Geng, Mengyuan, Wu, Yingjie, Bittner, Scott, Moulton, Hong M, Yin, HaiFang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863382/
https://www.ncbi.nlm.nih.gov/pubmed/33337582
http://dx.doi.org/10.15252/emmm.202012993
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author Ran, Ning
Lin, Caorui
Leng, Ling
Han, Gang
Geng, Mengyuan
Wu, Yingjie
Bittner, Scott
Moulton, Hong M
Yin, HaiFang
author_facet Ran, Ning
Lin, Caorui
Leng, Ling
Han, Gang
Geng, Mengyuan
Wu, Yingjie
Bittner, Scott
Moulton, Hong M
Yin, HaiFang
author_sort Ran, Ning
collection PubMed
description Antisense oligonucleotide (AO)‐mediated exon‐skipping therapies show promise in Duchenne muscular dystrophy (DMD), a devastating muscular disease caused by frame‐disrupting mutations in the DMD gene. However, insufficient systemic delivery remains a hurdle to clinical deployment. Here, we demonstrate that MOTS‐c, a mitochondria‐derived bioactive peptide, with an intrinsic muscle‐targeting property, augmented glycolytic flux and energy production capacity of dystrophic muscles in vitro and in vivo, resulting in enhanced phosphorodiamidate morpholino oligomer (PMO) uptake and activity in mdx mice. Long‐term repeated administration of MOTS‐c (500 μg) and PMO at the dose of 12.5 mg/kg/week for 3 weeks followed by 12.5 mg/kg/month for 3 months (PMO‐M) induced therapeutic levels of dystrophin expression in peripheral muscles, with up to 25‐fold increase in diaphragm of mdx mice over PMO alone. PMO‐M improved muscle function and pathologies in mdx mice without detectable toxicity. Our results demonstrate that MOTS‐c enables enhanced PMO uptake and activity in dystrophic muscles by providing energy and may have therapeutic implications for exon‐skipping therapeutics in DMD and other energy‐deficient disorders.
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spelling pubmed-78633822021-02-16 MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice Ran, Ning Lin, Caorui Leng, Ling Han, Gang Geng, Mengyuan Wu, Yingjie Bittner, Scott Moulton, Hong M Yin, HaiFang EMBO Mol Med Articles Antisense oligonucleotide (AO)‐mediated exon‐skipping therapies show promise in Duchenne muscular dystrophy (DMD), a devastating muscular disease caused by frame‐disrupting mutations in the DMD gene. However, insufficient systemic delivery remains a hurdle to clinical deployment. Here, we demonstrate that MOTS‐c, a mitochondria‐derived bioactive peptide, with an intrinsic muscle‐targeting property, augmented glycolytic flux and energy production capacity of dystrophic muscles in vitro and in vivo, resulting in enhanced phosphorodiamidate morpholino oligomer (PMO) uptake and activity in mdx mice. Long‐term repeated administration of MOTS‐c (500 μg) and PMO at the dose of 12.5 mg/kg/week for 3 weeks followed by 12.5 mg/kg/month for 3 months (PMO‐M) induced therapeutic levels of dystrophin expression in peripheral muscles, with up to 25‐fold increase in diaphragm of mdx mice over PMO alone. PMO‐M improved muscle function and pathologies in mdx mice without detectable toxicity. Our results demonstrate that MOTS‐c enables enhanced PMO uptake and activity in dystrophic muscles by providing energy and may have therapeutic implications for exon‐skipping therapeutics in DMD and other energy‐deficient disorders. John Wiley and Sons Inc. 2020-12-18 2021-02-05 /pmc/articles/PMC7863382/ /pubmed/33337582 http://dx.doi.org/10.15252/emmm.202012993 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Ran, Ning
Lin, Caorui
Leng, Ling
Han, Gang
Geng, Mengyuan
Wu, Yingjie
Bittner, Scott
Moulton, Hong M
Yin, HaiFang
MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice
title MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice
title_full MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice
title_fullStr MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice
title_full_unstemmed MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice
title_short MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice
title_sort mots‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863382/
https://www.ncbi.nlm.nih.gov/pubmed/33337582
http://dx.doi.org/10.15252/emmm.202012993
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