Glycine Enhances Satellite Cell Proliferation, Cell Transplantation, and Oligonucleotide Efficacy in Dystrophic Muscle

Lin, Caorui; Hou, Gang; Ning, Hanhan; Jiang, Song; Ran, Ning; Yi, Xianfu; Seow, Yiqi; Yin, HaiFang

doi:10.1016/j.ymthe.2020.03.003

Cited by 29 publications

(37 citation statements)

References 63 publications

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“…A study conducted in 2019 found that locked nucleic acid/2 -O-methyl mixmers increased exon skipping efficiency [73]. Another approach is to enhance target-tissue uptake using adjunctive components like glycine [74]. One important consideration in DMD therapy is the skipping efficacy in the cardiac muscles given that cardiomyopathy is the leading cause of death among DMD patients.…”

Section: Efficacy and Safety Of Aon-mediated Exon Skippingmentioning

confidence: 99%

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Sun

Shen

Zhang

et al. 2020

Genes

111

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Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.

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Section: Efficacy and Safety Of Aon-mediated Exon Skippingmentioning

confidence: 99%

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Sun

Shen

Zhang

et al. 2020

Genes

111

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“…However, there was no difference in dystrophin expression between mdx mice treated by PMO‐M with or without additional MOTS‐c (Fig 3B–D), suggesting that MOTS‐c potentiates PMO efficacy in mdx mice in a saturable manner. To investigate whether MOTS‐c can lower the systemic dose of PMO, we intravenously injected 500 μg MOTS‐c and PMO at a dose of 12.5 mg/kg/week for 3 weeks in mdx mice, a dose lower than those used in previous studies (Han et al , 2016; Lin et al , 2020). Surprisingly, significantly increased numbers of dystrophin‐positive myofibers and levels of dystrophin expression were found in peripheral muscles of mdx mice treated with PMO‐M compared to PMO alone under identical conditions (Fig 3E–H), further confirming the potency of MOTS‐c.…”

Section: Resultsmentioning

confidence: 99%

“…Since PMO‐M elicited effective dystrophin restoration at a lower dose, we wished to determine its long‐term efficacy in mdx mice with a dosing regimen similar to previous studies (Han et al , 2016; Lin et al , 2020), though the dose of PMO was reduced to 12.5 mg/kg (Fig 4A). Surprisingly, widespread expression of dystrophin over multiple tissue sections within each muscle group was detected in hind limb, forelimb, abdominal wall, and diaphragm muscles, but not in the heart of mdx mice treated with repeated injections of PMO‐M (Fig 4B and C).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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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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“…It has also been shown feasible to increase muscle delivery of AONs by formulating them in hexose solutions [60,61] or glycine solutions [62]. This increase was observed for both PMOs and 2OMePS AONs for hexose and, the effect was shown to be related to the metabolic state of the mdx muscle, which due to active and continuous muscle regeneration has a very high demand for nutrients.…”

Section: Chemical Modifications and Formulationsmentioning

confidence: 96%

“…For the glycine formulation, only PMOs were used. Here uptake is facilitated by the facts that glycine increases regeneration in mdx mice [62], and that PMOs rely on active regeneration for uptake [63].…”

Section: Chemical Modifications and Formulationsmentioning

confidence: 99%

Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy

Schneider

Aartsma‐Rus

2020

Expert Opinion on Biological Therapy

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Introduction: Exon skipping compounds restoring the dystrophin transcript reading frame have received regulatory approval for Duchenne muscular dystrophy (DMD). Recently, focus shifted to developing compounds to skip additional exons, improving delivery to skeletal muscle, and to genome editing, to restore the reading frame on DNA level. Areas covered: We outline developments for reading frame restoring approaches, challenges of mutation specificity, and optimizing delivery. Also, we highlight ongoing efforts to better detect exon skipping therapeutic effects in clinical trials. Searches on relevant terms were performed, focusing on recent publications (<3 years). Expert opinion: Currently, 3 AONS are approved. Whether dystrophin levels are sufficient to slowdown disease progression needs to be confirmed. Enhancing AON uptake by muscles is currently under investigation. Gene editing is an alternative, but one that involves practical and ethical concerns. Given the field's momentum, we believe the efficiency of frame-restoring approaches will improve.

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Glycine Enhances Satellite Cell Proliferation, Cell Transplantation, and Oligonucleotide Efficacy in Dystrophic Muscle

Cited by 29 publications

References 63 publications

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

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

Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy

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