Gene and cell‐mediated therapies for muscular dystrophy

Konieczny, Patryk; Swiderski, Kristy; Chamberlain, Jeffrey S.

doi:10.1002/mus.23738

Cited by 75 publications

(79 citation statements)

References 231 publications

(270 reference statements)

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“…Over time, repeated cycles of muscle degeneration/regeneration result in the exhaustion of the muscle progenitor pool and the failure of regenerative capacity. Multiple experimental approaches to treat DMD are currently under investigation, including exon skipping and stop codon readthrough, viral vector-mediated gene delivery, and cell therapy (32).…”

mentioning

confidence: 99%

Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis

Ljubicic

Burt

Lunde

et al. 2014

American Journal of Physiology-Cell Physiology

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Ljubicic V, Burt M, Lunde JA, Jasmin BJ. Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1␣ axis. Am J Physiol Cell Physiol 307: C66 -C82, 2014. First published April 24, 2014; doi:10.1152/ajpcell.00357.2013.-Slower, more oxidative muscle fibers are more resistant to the dystrophic pathology in Duchenne muscular dystrophy (DMD) patients as well as in the preclinical mdx mouse model of DMD. Therefore, one therapeutic strategy for DMD focuses on promoting expression of the slow, oxidative myogenic program. In the current study, we explored the therapeutic potential of stimulating the slow, oxidative phenotype in mdx mice by feeding 6-wk-old animals with the natural phenol resveratrol (RSV; ϳ100 mg·kg Ϫ1 ·day Ϫ1 ) for 6 wk. Sirtuin 1 (SIRT1) activity and protein levels increased significantly, as well as peroxisome proliferatoractivated receptor-␥ coactivator-1␣ (PGC-1␣) activity, in the absence of alterations in AMPK signaling. These adaptations occurred concomitant with evidence of a fast, glycolytic, to slower, more oxidative fiber type conversion, including mitochondrial biogenesis and increased expression of slower myosin heavy chain isoforms. These positive findings raised the question of whether increased exposure to RSV would result in greater therapeutic benefits. We discovered that an elevated RSV dose of ϳ500 mg·kg Ϫ1 ·day Ϫ1 across a duration of 12 wk was clearly less effective at muscle remodeling in mdx mice. This treatment protocol failed to influence SIRT1 or AMPK signaling and did not result in a shift towards a slower, more oxidative phenotype. Taken together, this study demonstrates that RSV can stimulate SIRT1 and PGC-1␣ activation, which in turn may promote expression of the slow, oxidative myogenic program in mdx mouse muscle. The data also highlight the importance of selecting an appropriate dosage regimen of RSV to maximize its potential therapeutic effectiveness for future application in DMD patients. DMD; SIRT1; utrophin A; PGC-1␣; AMPK DUCHENNE MUSCULAR DYSTROPHY (DMD) is a life-limiting, progressive muscle wasting disease that causes the loss of muscle function and independence. Genetic disruption of the dystrophin gene prevents the synthesis of the full-length dystrophin protein in skeletal muscle, which is the primary cause of the pathology (53). In the absence of dystrophin, the recruitment of the dystrophin-associated protein complex to the sarcolemma is impaired thereby creating a pathophysiological cascade with numerous adverse downstream events, including compromised sarcolemmal integrity, increased intracellular calcium, defective mitochondrial morphology, myofibrillar degradation, and ultimately death of the fibers (12). Over time, repeated cycles of muscle degeneration/regeneration result in the exhaustion of the muscle progenitor pool and the failure of regenerative capacity. Multiple experimental approaches to treat DMD are currently under investigation, including exon skipping and stop codo...

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confidence: 99%

Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis

Ljubicic

Burt

Lunde

et al. 2014

American Journal of Physiology-Cell Physiology

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“…Duchenne muscular dystrophy ( DMD ) is the most common monogenetic hereditary disorder, occurring in approximately 1 in 3500 male births [ 4 ]. This recessive, X-linked disorder is caused by mutations to the dystrophin gene.…”

Section: Duchenne and Becker Muscular Dystrophiesmentioning

confidence: 99%

“…The symptoms and progression of BMD are more diffi cult to predict than that of DMD, but typically follow a similar progressive muscular degeneration pattern, albeit at a much slower rate [ 4 ]. As a result, with proper care and disease management, most BMD patients can live independently and have a close to normal life expectancy.…”

Section: Duchenne and Becker Muscular Dystrophiesmentioning

confidence: 99%

Genome Editing for Neuromuscular Diseases

Ousterout

Gersbach

2016

Advances in Experimental Medicine and Biology

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Neuromuscular diseases are a diverse range of conditions that include myopathic and neuropathic disorders related to muscular dysfunction. Inherited neuromuscular diseases are the result of a broad spectrum of genetic mutations, including point mutations, insertions and deletions, chromosomal rearrangements, epigenetic aberrations, and repeat expansions or contractions. Targeted genome editing is a promising method to correct the inherited mutations underlying these disorders. Over the last decade there have been many signifi cant advances in engineering targeted DNA-binding proteins to manipulate specifi c sequences of complex genomes. These genome editing tools are rapidly becoming viable therapeutics that will allow the targeted addition, exchange, or removal of almost any genetic sequence in the human genome. In this chapter, selected neuromuscular diseases representing inherited myopathies or neuropathies are discussed. The genome editing tools available to create targeted genetic modifi cations are reviewed. Promising cell-and gene-based therapies are introduced in the context of the treatment of neuromuscular disorders in combination with genome editing therapies. Finally, specifi c examples of how genome editing may be applied to correct the genetic basis of particular neuromuscular disorders are presented and discussed.

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“…Current treatments of LGMD and DMD address the symptoms rather than the cause, although many promising strategies are emerging to replace the mutant gene or to facilitate skipping of the mutant exons to allow production of a partially functional dystrophin protein [5][6][7][8][9][10][11][12][13]. Detailed summaries of emerging therapies for these disorders are given in recent comprehensive reviews [14][15][16], as the present review focuses on stem cell therapy for DMD and LGMD.…”

Section: Muscular Dystrophy and The Rationale For Stem Cell Therapy Fmentioning

confidence: 99%

Concise Review: Mesoangioblast and Mesenchymal Stem Cell Therapy for Muscular Dystrophy: Progress, Challenges, and Future Directions

Berry

2014

Stem Cells Translational Medicine

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Mesenchymal stem cells (MSCs) and mesoangioblasts (MABs) are multipotent cells that differentiate into specialized cells of mesodermal origin, including skeletal muscle cells. Because of their potential to differentiate into the skeletal muscle lineage, these multipotent cells have been tested for their capacity to participate in regeneration of damaged skeletal muscle in animal models of muscular dystrophy. MSCs and MABs infiltrate dystrophic muscle from the circulation, engraft into host fibers, and bring with them proteins that replace the functions of those missing or truncated. The potential for systemic delivery of these cells increases the feasibility of stem cell therapy for the large numbers of affected skeletal muscles in patients with muscular dystrophy. The present review focused on the results of preclinical studies with MSCs and MABs in animal models of muscular dystrophy. The goals of the present report were to (a) summarize recent results, (b) compare the efficacy of MSCs and MABs derived from different tissues in restoration of protein expression and/or improvement in muscle function, and (c) discuss future directions for translating these discoveries to the clinic. In addition, although systemic delivery of MABs and MSCs is of great importance for reaching dystrophic muscles, the potential concerns related to this method of stem cell transplantation are discussed. STEM CELLS

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Gene and cell‐mediated therapies for muscular dystrophy

Cited by 75 publications

References 231 publications

Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis

Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis

Genome Editing for Neuromuscular Diseases

Concise Review: Mesoangioblast and Mesenchymal Stem Cell Therapy for Muscular Dystrophy: Progress, Challenges, and Future Directions

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