TitleMOTS-c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice.
Publication TypeJournal Article
Year of Publication2021
AuthorsRan, N, Lin, C, Leng, L, Han, G, Geng, M, Wu, Y, Bittner, S, Moulton, HM, Yin, H
JournalEMBO Mol Med
Date Published2021 Feb 05

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.

Alternate JournalEMBO Mol Med
PubMed ID33337582
PubMed Central IDPMC7863382
Grant List2017YFC1001902 / / National Key R&D Programme of China /
81672124 / / National Natural Science Foundation of China (NSFC) /
82030054 / / National Natural Science Foundation of China (NSFC) /
81802124 / / National Natural Science Foundation of China (NSFC) /