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. 2013 Oct 9;74(3):404–411. doi: 10.1002/ana.23989

Therapeutic advances in muscular dystrophy

Doris G Leung 1,2, Kathryn R Wagner 1,2,3,1
PMCID: PMC3886293  PMID: 23939629

Abstract

The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Each of these disorders represents a different class of genetic disease (monogenic, epigenetic, and repeat expansion disorders), and the approach to therapy addresses the diverse and complex molecular mechanisms involved in these diseases. The large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggests there will be an improved quality of life for individuals with muscular dystrophy.

The muscular dystrophies are genetic disorders that cause progressive wasting and weakness of skeletal muscle. Although each of the individual muscular dystrophies is relatively rare, they collectively affect millions of people worldwide. The estimated prevalence rates of the most common forms of muscular dystrophy are 1 in 5,000 live male births for Duchenne muscular dystrophy (DMD) and between 1 in 7,000 and 1 in 20,000 for both facioscapulohumeral muscular dystrophy (FSHD) and myotonic muscular dystrophy.1–5 These disorders are often profoundly disabling due to loss of mobility and the increased incidence of medical comorbidities, such as heart disease and respiratory failure. The burden of disease and disability is carried not only by patients, but by caregivers and families. Although the cost of care for these disorders is likely to vary worldwide, the limited utilization data available make it clear that many in this patient population do not have access to the standards of care recommended for these diseases.6,7

Finding effective treatments for the muscular dystrophies has proven challenging, in part due to their heterogeneity. They are caused by mutations in >30 unique genes that produce myofiber degeneration and atrophy. Traditionally, muscular dystrophies have been defined by their clinical manifestations: distribution of weakness, mode of inheritance, onset and progression of disease, and distinctive nonskeletal muscle features. Genotyping of this patient population has challenged this convention, as it has been proven that the phenotypic spectrum of these disorders is much wider than previously suspected. Similar or identical mutations in a single gene can produce widely disparate phenotypes, even within the same family.9,10 Conversely, increasing numbers of distinct genes have been found to produce the same phenotype, such as the classic limb-girdle pattern of weakness. These discoveries have compelled the reclassification of genetic myopathies by their molecular deficits (eg, dystroglycanopathies, dysferlinopathies, laminopathies, ion channelopathies) in addition to their clinical features. This rethinking will ultimately improve our ability to develop targeted disease-modifying therapy and to define subsets of the population that are likely to respond to these treatments. It will also allow us to identify potential therapies for the muscular dystrophies through investigations of nonmuscle disorders that share the same genetic mechanism.

In this review, we will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy. These disorders represent distinct classes of genetic disease: DMD is a single-gene, loss-of-function disorder, FSHD is an epigenetic disorder, and myotonic dystrophy is a repeat expansion disorder with toxic gain of function. By addressing the muscular dystrophies in this way, we hope to illustrate the need for mechanistic diversity in our research pursuits and in our approach toward treating the individual patient.

Modern Understanding of Biology

DMD

DMD and the milder, allelic Becker muscular dystrophy (BMD) represent a spectrum of disorders that stem from a loss of functional dystrophin protein. Since its discovery in the mid-1980s, there has been significant progress in determining the function of dystrophin and the biochemical consequences of its loss. Dystrophin not only has a structural role in linking the muscle cytoskeleton to the extracellular matrix, it also plays a prominent role in cell signaling and regulating muscle response to oxidative stress.12 The absence of dystrophin impedes the muscle's ability to tolerate conformational changes induced by contraction.13 The resultant muscle degeneration and inflammatory response produce a cellular environment in which adipocytes and fibroblasts proliferate and impair the regenerative capacity of muscle precursor cells.14 Advances in research in the dystrophinopathies have placed them at the forefront of exploration in the classic single-gene, loss-of-function disorders. Multiple therapeutic approaches to this disease (inducing dystrophin expression, preventing the downstream effects of muscle degeneration, and promoting muscle growth or replacement) are being explored in preclinical and clinical trials.

FSHD

The past few years have proven to be a watershed period in the understanding of FSHD. Although a deletion in the D4Z4 macrosatellite repeat array of chromosome 4 was known to be associated with FSHD, we have only recently begun to understand how this change causes disease.15–16 It is now apparent that the underlying mechanism of FSHD involves a complex convergence of both genetic and epigenetic events. The contraction of the D4Z4 array is associated with hypomethylation of this region and chromatin relaxation that enables the transcription of DUX4, a gene that is normally suppressed after early development.17 DUX4 mRNA is rapidly degraded unless it is transcribed in the context of specific haplotypes that contain a polyadenylation signal.18,19 Expression of full-length DUX4 protein occurs in approximately 1 in 1,000 myocytes in vitro and induces transcription of germline genes and endogenous retrotransposons that are not normally expressed in adult skeletal muscle.21 The function of DUX4 and how it contributes to muscle pathology are not fully understood. Full-length DUX4 RNA is not always detectable in muscle tissue from FSHD patients, and it is present in some unaffected individuals with normal D4Z4 repeat arrays, suggesting that a second factor or mutation is required for pathogenesis.21–22 The recent discovery of a causative gene (SMCHD1) for FSHD2 (a disease identical to FSHD in terms of phenotype and chromosome 4q hypomethylation, but without contraction of the D4Z4 array) also supports a 2-hit hypothesis and further highlights the importance of both the genetic and epigenetic aspects of this disease.23,24

Myotonic Dystrophy

The discovery of the microsatellite repeat expansion disorders provides further evidence of the importance of noncoding DNA and RNA function in muscle and other tissues. Myotonic dystrophy owes its multisystemic clinical phenotype to the widespread impact of repetitive code sequences on multiple cellular pathways. There have been 2 genetically distinct forms of myotonic dystrophy identified (type 1 is due to a trinucleotide repeat expansion of the DMPK gene on chromosome 19, and type 2 is associated with a 4-nucleotide repeat in the ZNF9 gene on chromosome 3).26,27 These mutations interfere with RNA-binding proteins, leading to increased levels of CUGBP1/Elav-like family member 1 (CELF1) and decreased levels of muscleblind-like proteins (MBNLs), which are sequestered in ribonuclear foci. This results in mis-splicing of multiple genes, including ClCN1, which encodes the muscle chloride channel type 1 (leading to myotonia), the insulin receptor (leading to insulin resistance), and TNNT2, which encodes troponin T type 2 (potentially important in cardiac pathology),29–32 among others. In addition to inducing a “sliceopathy,” the repeat expansions may also induce disease through altered function of DMPK and ZNF9, dysregulated expression of neighboring genes, and repeat associated non-ATG translation.33–36 Recent studies have also begun to elucidate the role of repeat expansions in the central nervous system (CNS) manifestations of myotonic dystrophy, including cognitive dysfunction and sleep disorders.37,38

Currently Available Therapies

Given the physical disability inherent in muscle disease and the multisystemic medical complications that can be associated with muscular dystrophies, the medical requirements in this patient population are formidable. The interdisciplinary management of physicians, therapists, counselors, and other specialists has extended the life expectancy of patients with muscular dystrophy considerably.40–41 Supportive care for the muscular dystrophy population may involve multiple nonpharmacologic interventions, including physical therapy, occupational therapy, orthopedic surgery, genetic counseling, invasive and noninvasive mechanical ventilation, and the use of implanted cardiac devices.42–43 However, pharmacologic disease-modifying treatments remain limited. In DMD, only corticosteroids have been shown to improve skeletal muscle strength and function in reproducible randomized controlled trials.44,45 Other pharmacologic therapies are primarily directed toward managing comorbidities (such as cardiomyopathy, osteoporosis, and respiratory failure).

Therapeutic Pipeline in 2013

DMD

Inducing Dystrophin Expression

Several therapeutic approaches to DMD are designed to promote endogenous dystrophin expression. One of the most novel and promising approaches is exon skipping, which utilizes antisense oligonucleotides (AONs) to promote alternative exon splicing and restore the open reading frame of dystrophin mRNA.47 The product of this technique is an altered but functional version of dystrophin that would predict a milder Becker, rather than Duchenne, phenotype. Two experimental drugs, eteplirsen (Sarepta Therapeutics, Cambridge, MA) and drisapersen (Prosensa Therapeutics, Leiden, the Netherlands and GlaxoSmithKline, Brentford, UK), are both designed to induce skipping of exon 51 (applicable to approximately 16% of DMD patients) and are being tested in phase II/III clinical trials.48,49 Although their oligonucleotide chemistries and side effect profiles differ, clinical trial data for both drugs show increased dystrophin expression in skeletal muscle biopsies of treated subjects. Even more impressively, subjects randomized to both study drugs had improved muscle function (measured by the 6-minute walk distance) compared to those randomized to placebo.51 A recent small molecule screen identified dantrolene (a drug approved by the US Food and Drug Administration for malignant hyperthermia) as a potential enhancer of exon skipping. Further studies in mice and reprogrammed human myotubes demonstrated that dantrolene given in conjunction with AONs increases levels of exon skipping by an order of magnitude and improves both dystrophin expression and muscle strength in mdx mice.52 Given the variability of dystrophin expression seen in exon skipping trials, the potential toxicities of AONs, and the high anticipated cost of AON administration, adjunctive measures that enhance exon skipping or lower the effective dose of these drugs will be clinically significant.

Approximately 10 to 15% of mutations in the DMD population are nonsense mutations that produce premature stop codons in dystrophin mRNA that result in no dystrophin expression or truncated proteins that are rapidly degraded. Aminoglycosides, such as gentamicin, allow the translational machinery to read through these stop codons, thereby producing full-length proteins.53–54 Although a 2-week trial of daily gentamicin in DMD/BMD failed to show dystrophin expression, a 6-month trial of weekly gentamicin demonstrated increased dystrophin expression in DMD boys with nonsense mutations.55–56 Due to dose-limiting toxicities of aminoglycosides, novel agents inducing readthrough have been sought. Ataluren (previously PTC124; PTC Therapeutics, South Plainfield, NJ) is an orally administered small molecule that is being evaluated for a number of disorders with nonsense mutations, including cystic fibrosis and DMD. Although ataluren has been described as increasing dystrophin expression and decreasing pathology in the mdx mouse, subsequent independent studies have questioned whether ataluren induces readthrough.57,58 Phase II clinical trials of ataluren in DMD have shown a good safety profile and a slower decline in 6-minute walk distances in a low-dose cohort (compared to placebo); however, no improvement in the 6-minute walk distance was observed in a high-dose cohort.60 A phase III trial of ataluren in ambulatory DMD patients is currently enrolling (ClinicalTrials.gov NCT01826487) and will hopefully provide definitive answers regarding its efficacy.

Introducing a functional dystrophin gene into dystrophic muscle cells has been a therapeutic goal since the discovery of the molecular basis of DMD in the 1980s. Numerous challenges have delayed the clinical implementation of this approach beyond initial expectations. However, using adeno-associated viral (AAV) vectors, investigators have succeeded in transducing both skeletal and cardiac muscle with modified forms of dystrophin (mini-dystrophins) in animal models of DMD.61–62 A phase I gene therapy trial using AAV 2.5 delivery of a mini-dystrophin gene supports the safety and tolerability of intramuscular delivery; however, dystrophin expression was limited.63,64 Since this first gene therapy trial in DMD, advances have been made in vector design, muscle-specific promoters, and mini-dystrophin constructs. It is anticipated that the safety of regional delivery will need to be established before systemic gene replacement in DMD can be achieved. The safety and feasibility of high-pressure transvenous limb perfusion with saline has recently been demonstrated in BMD, facilitating upcoming trials in the regional delivery of viral vectors.66

Muscle Regeneration and Replacement

Given the large number of individual mutations that can cause dystrophinopathy, it is important to explore therapeutic options that can improve muscle pathology but are not mutation-specific. Stem cell transplantation is an attractive option in this category that would be applicable not only to DMD but to the myriad other muscular dystrophies as well. Direct transplantation of myogenic precursor cells (MPCs) has proven difficult, and efforts to promote the migration, expansion, differentiation, and survival of these cells in vivo are ongoing.67 Transplantation of mesoangioblasts (vascular-derived stem cells) has demonstrated benefit in animal models of DMD and is currently in phase I human trials.68 Pharmacologic agents that induce muscle regeneration, such as myostatin inhibitors and insulinlike growth factor 1 (IGF-1), continue to be developed as solo therapy for the dystrophinopathies and other chronic myopathies. These agents will likely prove beneficial in conjunction with MPC transplantation not only for their ability to stimulate MPC proliferation and differentiation but also for their ability to reduce fibrosis.69,70

Modulating Signaling Pathways

Disruption of the dystrophin scaffold alters key signaling pathways necessary for muscle health and function. An especially important signaling protein is neuronal nitric oxide synthase (nNOS). One of the functions of sarcolemmal nNOSμ (the muscle-specific form of this enzyme) is local regulation of vascular flow during exercise; nitric oxide (NO) promotes smooth muscle relaxation and vasodilation. NO also regulates cardiac, skeletal, and smooth muscle contractile function and modulates the immune response in muscle. The major signaling pathway for NO is stimulation of cyclic guanosine monophosphate (cGMP) production by soluble guanylyl cyclase (sGC). In turn, cGMP directly activates protein kinase G (PKG) and certain ion channels. The NO-cGMP-PKG pathway is disrupted in muscular dystrophy, beginning with reduction in nNOS activity. Phosphodiesterases (PDEs) hydrolyze cGMP and turn down the gain of NO-cGMP signaling. Amplification of NO-cGMP signaling by administration of the PDE5A inhibitor sildenafil reduces functional deficits in cardiac performance and skeletal muscle pathology and function in aged mdx mice.72–73 The nNOS signaling pathway is a potential therapeutic target not only for DMD, but for multiple other muscular dystrophies in which nNOSμ is also mislocalized. Clinical trials are being conducted to investigate various phosphodiesterase inhibitors and novel agents that modulate the NO-cGMP-PKG pathway (ClinicalTrials.gov NCT01359670, NCT01168908, NCT01865084).74

Inhibition of Fibrosis

One of the late effects of muscle degeneration in DMD is replacement of muscle with fat and fibrosis.75 Fibrosis impedes muscle regeneration and may make several of the above therapeutics ineffective. Mechanisms to prevent or possibly reverse fibrosis include myostatin inhibition, transforming growth factor β (TGF-β) inhibition, and halofuginone, a novel drug that may exert its effects through the TGF-β pathway.76–77 Several clinical trials are planned or underway to determine the efficacy of compounds that are directed at inhibiting the formation of fibrotic tissue (ClinicalTrials.gov NCT01847573).

FSHD

The identification of the DUX4 gene as a mediator of disease in FSHD opens up new possibilities for targeted therapy. DUX4 encodes a transcription factor that is believed to be involved in myogenic differentiation, and its anomalous expression in adult muscle in FSHD provides an attractive target for knockdown or inhibitory therapies. The role of DNA methylation and chromatin restructuring in FSHD also introduces the possibility that therapies that are being investigated in other epigenetic disorders will have utility in the treatment of FSHD.78 Clinical trials are being considered to determine the efficacy of several pharmacologic compounds—including selective androgen receptor modulators, myostatin inhibitors, and troponin activators—in the FSHD population. Although these therapies are not targeted toward the genetic mechanism that produces FSHD, there is evidence that they may promote muscle growth and/or improve skeletal muscle function.

Myotonic Dystrophy

The pathology induced by DNA and RNA expansion in the myotonic dystrophies may be uniquely suited to therapeutic modification through antisense technologies. Some ways in which antisense therapy could reverse the pathology of myotonic dystrophy include: neutralization of binding sites for RNA-binding proteins, promoting targeted degradation of repeat expansion mRNA, and reduction in the size of the trinucleotide expansion. The latter mechanism is of particular interest, as the number of CTG repeats in the DMPK gene correlates with some aspects of disease severity in type I myotonic dystrophy.79 Therapies may also be directed toward the known downstream regulators of disease, such as MBNL1 and CELF1.80 In considering potential therapies for myotonic dystrophy, however, it is important to recognize that the CNS manifestations of this disease (executive dysfunction, intellectual disability, sleep dysregulation), are frequently more disabling than muscle weakness.81–82 In this sense, investigation in the treatment of the myotonic dystrophies may benefit from growing research in other genetic disorders that affect the CNS (spinal muscular atrophy, amyotrophic lateral sclerosis/frontotemporal dementia secondary C9orf72 mutations, Huntington disease, and the spinocerebellar ataxias).83–84

Unmet Needs

As with all diseases that are severely debilitating and incurable, the need for treatment options in the muscular dystrophy population is manifest. As new therapeutic options enter into development, both investigators and patient groups recognize the need to facilitate and expedite clinical trials. To further this goal, it will be important to characterize the current natural history of these diseases and to develop outcome measures specific to the muscular dystrophy population. The most appropriate outcome measures will likely include clinical measurements and patient-reported outcomes as well as more novel imaging and biochemical disease markers. The identification, organization, and stratification of patient groups through registries and the collection of clinical and genotype data will also be important aspects of clinical trial preparedness.85–86 Further research on medical management and standards of care is also a significant unmet need in the muscular dystrophy population. There is considerable variability in the clinical management of these diseases, and studies are underway to help us better understand the risks and benefits of medical interventions (such as the various corticosteroid dosing regimens) and to make better-informed treatment recommendations.87

The management of the muscular dystrophies relies heavily on nonpharmacologic interventions that span multiple disciplines. Of particular interest to this patient population is the role of physical therapy, exercise, and other muscle stimulation techniques that can utilize endogenous mechanisms of muscle growth.88–89 This issue is controversial, as efforts to increase muscle strength through exercise may be countered by the risk of overuse and excessive breakdown of muscle that has limited regenerative capacity.90–91 Numerous studies have examined a variety of exercise programs in small numbers of patients with various types of muscular dystrophy, and there is evidence that some of these programs can be performed safely and at least temporarily improve muscle function.92–93 However, the lack of uniformity in exercise protocols and outcome measures has been a limiting factor in the development of widely applicable exercise guidelines.94–95 Although there is a demand for guidance on the relative benefits and potential harms (both medical and financial) of the numerous physical therapy options that confront patients, many of these interventions cannot be easily studied and measured under the methodologies that produce the highest levels of evidence (adequately powered, randomized placebo-controlled trials). Greater ingenuity in study design and data analysis is needed to understand their contribution to muscle health and to formulate guidelines on their use.

Possible New Directions for Research

It is important to recognize that the optimal treatment for patients with muscular dystrophy may not take the form of a single drug or treatment modality, but rather a combination of treatments that address different pathological processes or act synergistically within the same pathway. Some of these possible complementary approaches are discussed here.

An important finding from a recent gene therapy trial (using AAV vectors carrying mini-dystrophin) was that an immune reaction to dystrophin occurred in some patients.64,96 Two of 6 subjects had dystrophin-specific T-cell responses prior to treatment consistent with priming, perhaps by rare revertant myofibers expressing dystrophin. As yet, there have been no reports of this phenomenon in other DMD trials (including those for exon skipping). However, if dystrophin-specific T-cell responses are found to occur frequently with induced dystrophin expression, it has broad implications not only for gene therapy, but for other genetic modifications and stem cell transplantation. An immune response to the vector capsid or transgene need not be insurmountable given the many tolerable immunomodulatory and immunosuppressive treatments available.

Increasing evidence in stem cell research has suggested that numerous factors in the local milieu promote or impair successful transplantation. Modulating the immune response against MPC grafts while providing a hospitable environment will improve the survival, migration, and differentiation of transplanted cells.98–99 Factors that inhibit fibrosis and promote muscle growth (such as myostatin inhibitors and IGF-1) may complement and enhance the efficacy of MPC transplants. The use of 3-dimensional scaffolds may also allow MPCs to differentiate into myotubes more successfully than single cells dispersed within fibrotic muscle tissue. Bioengineering of muscle tissue is advancing at an exciting pace as a treatment for traumatic injuries and has the potential to benefit those with muscular dystrophy as well.

In addition to continued pursuit of safe and effective pharmacologic agents that induce readthrough of premature stop codons, the field needs a better understanding of nonsense-mediated decay as it relates to the dystrophin transcript. Nonsense-mediated decay is a system of RNA surveillance that causes the degradation of mRNA with premature stop codons, abnormally spliced mRNA, and selected full-length mRNA transcripts. This is a highly conserved regulatory function designed to prevent expression of aberrant proteins and mediate the cellular response to stress.100 The rapidity with which nonsense-mediated decay occurs may limit the availability of transcripts that are targeted by drugs that promote nonsense readthrough. If so, inhibition of nonsense-mediated decay may be needed for these therapies to be efficacious. Although compounds that inhibit nonsense-mediated decay in vitro have been identified, they have not yet been tested for this purpose in humans.101

Conclusions

The future of muscular dystrophy research promises to be both dynamic and productive, as great strides have been made in our understanding of the mechanisms underlying these diseases. These advances in knowledge are reflected in the proliferation of clinical trials and observational studies directed toward clinical trial preparedness. Muscular dystrophy patients now have an unprecedented number of pharmacotherapeutic trials available to them. In a field where the traditional approach to treatment has often been one of resignation and sympathetic fatalism, this new opportunity for optimism and intervention is both revolutionary and welcome.

Potential Conflicts of Interest

Nothing to report.

References

  1. Moat SJ, Bradley DM, Salmon R, Clarke A, Hartley L. Newborn bloodspot screening for Duchenne muscular dystrophy: 21 years experience in Wales (UK) Eur J Hum Genet. doi: 10.1038/ejhg.2012.301. 2013 Jan 23. doi: 10.1038/ejhg.2012.301 [Epub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Mendell JR, Shilling C, Leslie ND, et al. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol. 2012;71:304–313. doi: 10.1002/ana.23528. [DOI] [PubMed] [Google Scholar]
  3. Emery AE. Population frequencies of inherited neuromuscular diseases—a world survey. Neuromuscul Disord. 1991;1:19–29. doi: 10.1016/0960-8966(91)90039-u. [DOI] [PubMed] [Google Scholar]
  4. Mendell JR, Lloyd-Puryear M. Report of MDA muscle disease symposium on newborn screening for Duchenne muscular dystrophy. Muscle Nerve. 2013;48:21–26. doi: 10.1002/mus.23810. [DOI] [PubMed] [Google Scholar]
  5. Aymé S, Gonthier C. Prevalence of rare diseases: bibliographic data. Orphanet Report Series Rare Diseases Collection. 2011;1:1–29. [Google Scholar]
  6. Ouyang L, Grosse SD, Kenneson A. Health care utilization and expenditures for children and young adults with muscular dystrophy in a privately insured population. J Child Neurol. 2008;23:883–888. doi: 10.1177/0883073808314962. [DOI] [PubMed] [Google Scholar]
  7. Muscular Dystrophy Association. The cost of muscular dystrophy. Canberra, Australia: Access Economics; 2007. [Google Scholar]
  8. Larkindale J, Yang W, Hogan PF, Simon CJ, Zhang Y, Jain A, Habeeb-Louks EM, Kennedy A, Cwik VA. Cost of illness for neuromuscular diseases in the U.S. Muscle Nerve. doi: 10.1002/mus.23942. 2013 Jul 8. doi: 10.1002/mus.23942. [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
  9. Godfrey C, Clement E, Mein R, et al. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain. 2007;130(pt 10):2725–2735. doi: 10.1093/brain/awm212. [DOI] [PubMed] [Google Scholar]
  10. Nguyen K, Bassez G, Krahn M, et al. Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes. Arch Neurol. 2007;64:1176–1182. doi: 10.1001/archneur.64.8.1176. [DOI] [PubMed] [Google Scholar]
  11. Stensland E, Lindal S, Jonsrud C, et al. Prevalence, mutation spectrum and phenotypic variability in Norwegian patients with limb girdle muscular dystrophy 2I. Neuromuscul Disord. 2011;21:41–46. doi: 10.1016/j.nmd.2010.08.008. [DOI] [PubMed] [Google Scholar]
  12. Brenman JE, Chao DS, Xia H, et al. Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy. Cell. 1995;82:743–752. doi: 10.1016/0092-8674(95)90471-9. [DOI] [PubMed] [Google Scholar]
  13. Petrof BJ, Shrager JB, Stedman HH, et al. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A. 1993;90:3710–3714. doi: 10.1073/pnas.90.8.3710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Klingler W, Jurkat-Rott K, Lehmann-Horn F, Schleip R. The role of fibrosis in Duchenne muscular dystrophy. Acta Myol. 2012;31:184–195. [PMC free article] [PubMed] [Google Scholar]
  15. van Deutekom JC, Wijmenga C, van Tienhoven EA, et al. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet. 1993;2:2037–2042. doi: 10.1093/hmg/2.12.2037. [DOI] [PubMed] [Google Scholar]
  16. Wijmenga C, Hewitt JE, Sandkuijl LA, et al. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet. 1992;2:26–30. doi: 10.1038/ng0992-26. [DOI] [PubMed] [Google Scholar]
  17. Snider L, Geng LN, Lemmers RJ, et al. Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PloS Genet. 2010;6:e1001181. doi: 10.1371/journal.pgen.1001181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lemmers RJ, Wohlgemuth M, van der Gaag KJ, et al. Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2007;81:884–894. doi: 10.1086/521986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Thomas NS, Wiseman K, Spurlock G, et al. A large patient study confirming that facioscapulohumeral muscular dystrophy (FSHD) disease expression is almost exclusively associated with an FSHD locus located on a 4qA-defined 4qter subtelomere. J Med Genet. 2007;44:215–218. doi: 10.1136/jmg.2006.042804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lemmers RJLF, van der Vliet PJ, Klooster R, et al. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010;329:1650–1653. doi: 10.1126/science.1189044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Geng LN, Yao Z, Snider L, et al. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell. 2012;22:38–51. doi: 10.1016/j.devcel.2011.11.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jones TI, Chen JC, Rahimov F, et al. Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis. Hum Mol Genet. 2012;21:4419–4430. doi: 10.1093/hmg/dds284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lemmers RJ, Tawil R, Petek LM, et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012;44:1370–1374. doi: 10.1038/ng.2454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. de Greef JC, Lemmers RJ, van Engelen BG, et al. Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD. Hum Mutat. 2009;30:1449–1459. doi: 10.1002/humu.21091. [DOI] [PubMed] [Google Scholar]
  25. Hartweck LM, Anderson LJ, Lemmers RJ, et al. A focal domain of extreme demethylation within D4Z4 in FSHD2. Neurology. 2013;80:392–399. doi: 10.1212/WNL.0b013e31827f075c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Brook JD, McCurrach ME, Harley HG, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell. 1992;68:799–808. doi: 10.1016/0092-8674(92)90154-5. [DOI] [PubMed] [Google Scholar]
  27. Mahadevan M, Tsilfidis C, Sabourin L, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science. 1992;255:1253–1258. doi: 10.1126/science.1546325. [DOI] [PubMed] [Google Scholar]
  28. Liquori CL, Ricker K, Moseley ML, et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001;293:864–867. doi: 10.1126/science.1062125. [DOI] [PubMed] [Google Scholar]
  29. Mankodi A, Takahashi MP, Jiang H, et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell. 2002;10:35–44. doi: 10.1016/s1097-2765(02)00563-4. [DOI] [PubMed] [Google Scholar]
  30. Savkur RS, Philips AV, Cooper TA, et al. Insulin receptor splicing alteration in myotonic dystrophy type 2. Am J Hum Genet. 2004;74:1309–1313. doi: 10.1086/421528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Dansithong W, Paul S, Comai L, Reddy S. MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1. J Biol Chem. 2005;280:5773–5780. doi: 10.1074/jbc.M410781200. [DOI] [PubMed] [Google Scholar]
  32. Ho TH, Bundman D, Armstrong DL, Cooper TA. Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy. Hum Mol Genet. 2005;14:1539–1547. doi: 10.1093/hmg/ddi162. [DOI] [PubMed] [Google Scholar]
  33. Ebralidze A, Wang Y, Petkova V, et al. RNA leaching of transcription factors disrupts transcription in myotonic dystrophy. Science. 2004;303:383–387. doi: 10.1126/science.1088679. [DOI] [PubMed] [Google Scholar]
  34. Mahadevan MS, Yadava RS, Yu Q, et al. Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nat Genet. 2006;38:1066–1070. doi: 10.1038/ng1857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zu T, Gibbens B, Doty NS, et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. 2011;108:260–265. doi: 10.1073/pnas.1013343108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Davis BM, McCurrach ME, Taneja KL, et al. Expansion of a CUG trinucleotide repeat in the 3′ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. Proc Natl Acad Sci U S A. 1997;94:7388–7393. doi: 10.1073/pnas.94.14.7388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Charizanis K, Lee KY, Batra R, et al. Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy. Neuron. 2012;75:437–450. doi: 10.1016/j.neuron.2012.05.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Dhaenens CM, Tran H, Frandemiche ML, et al. Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing. Biochim Biophys Acta. 2011;1812:732–742. doi: 10.1016/j.bbadis.2011.03.010. [DOI] [PubMed] [Google Scholar]
  39. Suenaga K, Lee KY, Nakamori M, et al. Muscleblind-like 1 knockout mice reveal novel splicing defects in the myotonic dystrophy brain. PLoS One. 2012;7:e33218. doi: 10.1371/journal.pone.0033218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Eagle M, Baudouin S, Chandler C, et al. Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromusc Disord. 2002;12:926–929. doi: 10.1016/s0960-8966(02)00140-2. [DOI] [PubMed] [Google Scholar]
  41. Passamano L, Taglia A, Palladino A, et al. Improvement of survival in Duchenne muscular dystrophy: retrospective analysis of 835 patients. Acta Myol. 2012;31:121–125. [PMC free article] [PubMed] [Google Scholar]
  42. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9:77–93. doi: 10.1016/S1474-4422(09)70271-6. [DOI] [PubMed] [Google Scholar]
  43. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 2010;9:177–189. doi: 10.1016/S1474-4422(09)70272-8. [DOI] [PubMed] [Google Scholar]
  44. Mendell JR, Moxley RT, Griggs RC, et al. Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy. N Engl J Med. 1989;320:1592–1597. doi: 10.1056/NEJM198906153202405. [DOI] [PubMed] [Google Scholar]
  45. Biggar WD, Harris VA, Eliasoph L, Alman B. Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromusc Disord. 2006;16:249–255. doi: 10.1016/j.nmd.2006.01.010. [DOI] [PubMed] [Google Scholar]
  46. Griggs RC, Moxley RT, III, Mendell JR, et al. Prednisone in Duchenne dystrophy: a randomized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group. Arch Neurol. 1991;48:383–388. doi: 10.1001/archneur.1991.00530160047012. [DOI] [PubMed] [Google Scholar]
  47. Dunckley MG, Manoharan M, Villiet P, et al. Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides. Hum Mol Genet. 1998;7:1083–1090. doi: 10.1093/hmg/7.7.1083. [DOI] [PubMed] [Google Scholar]
  48. Kinali M, Arechavala-Gomeza V, Feng L, et al. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 2009;8:918–928. doi: 10.1016/S1474-4422(09)70211-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Cirak S, Arechavala-Gomeza V, Guglieri M, et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet. 2011;378:595–605. doi: 10.1016/S0140-6736(11)60756-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. van Deutekom JC, Janson AA, Ginjaar IB, et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med. 2007;357:2677–2686. doi: 10.1056/NEJMoa073108. [DOI] [PubMed] [Google Scholar]
  51. Goemans NM, Tulinius M, van den Akker JT, et al. Systemic administration of PRO051 in Duchenne's muscular dystrophy. N Engl J Med. 2011;364:1513–1522. doi: 10.1056/NEJMoa1011367. [DOI] [PubMed] [Google Scholar]
  52. Kendall GC, Mokhonova EI, Moran M, et al. Dantrolene enhances antisense-mediated exon skipping in human and mouse models of Duchenne muscular dystrophy. Sci Transl Med. 2012;4:164ra160. doi: 10.1126/scitranslmed.3005054. [DOI] [PubMed] [Google Scholar]
  53. Burke JF, Mogg AE. Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G-418 and paromomycin. Nucleic Acids Res. 1985;13:6265–6272. doi: 10.1093/nar/13.17.6265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Barton-Davis ER, Cordier L, Shoturma DI, et al. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest. 1999;104:375–381. doi: 10.1172/JCI7866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Wagner KR, Hamed S, Hadley DW, et al. Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations. Ann Neurol. 2001;49:706–711. [PubMed] [Google Scholar]
  56. Malik V, Rodino-Klapac LR, Viollet L, et al. Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy. Ann Neurol. 2010;67:771–780. doi: 10.1002/ana.22024. [DOI] [PubMed] [Google Scholar]
  57. Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447:87–91. doi: 10.1038/nature05756. [DOI] [PubMed] [Google Scholar]
  58. Auld DS, Thorne N, Maguire WF, Inglese J. Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression. Proc Natl Acad Sci U S A. 2009;106:3585–3590. doi: 10.1073/pnas.0813345106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. McElroy SP, Nomura T, Torrie LS, et al. A lack of premature termination codon read-through efficacy of PTC124 (ataluren) in a diverse array of reporter assays. PLoS Biol. 2013;11:e1001593. doi: 10.1371/journal.pbio.1001593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Finkel R, Wong B, Bushby K, et al. Results of a phase 2b, dose-ranging study of ataluren (PTC124 (R)) in nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD) Neuromuscul Disord. 2010;20:656–657. [Google Scholar]
  61. Shin JH, Pan X, Hakim CH, et al. Microdystrophin ameliorates muscular dystrophy in the canine model of Duchenne muscular dystrophy. Mol Ther. 2013;21:750–757. doi: 10.1038/mt.2012.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Konieczny P, Swiderski K, Chamberlain JS. Gene and cell-mediated therapies for muscular dystrophy. Muscle Nerve. 2013;47:649–663. doi: 10.1002/mus.23738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Bowles DE, McPhee SW, Li C, et al. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol Ther. 2012;20:443–455. doi: 10.1038/mt.2011.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Mendell JR, Campbell K, Rodino-Klapac L, et al. Dystrophin immunity in Duchenne's muscular dystrophy. N Engl J Med. 2010;363:1429–1437. doi: 10.1056/NEJMoa1000228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Mendell JR, Rodino-Klapac L, Sahenk Z, et al. Gene therapy for muscular dystrophy: lessons learned and path forward. Neurosci Lett. 2012;527:90–99. doi: 10.1016/j.neulet.2012.04.078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Fan Z, Kocis K, Valley R, et al. Safety and feasibility of high-pressure transvenous limb perfusion with 0.9% saline in human muscular dystrophy. Mol Ther. 2012;20:456–461. doi: 10.1038/mt.2011.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Briggs D, Morgan JE. Recent progress in satellite cell/myoblast engraftment—relevance for therapy. FEBS J. 2013;280:4281–4293. doi: 10.1111/febs.12273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Sampaolesi M, Blot S, D'Antona G, et al. Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature. 2006;444:574–579. doi: 10.1038/nature05282. [DOI] [PubMed] [Google Scholar]
  69. Fakhfakh R, Lee SJ, Tremblay JP. Administration of a soluble activin type IIB receptor promotes the transplantation of human myoblasts in dystrophic mice. Cell Transplant. 2012;21:1419–1430. doi: 10.3727/096368911X627480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Shavlakadze T, White J, Hoh JF, et al. Targeted expression of insulin-like growth factor-I reduces early myofiber necrosis in dystrophic mdx mice. Mol Ther. 2004;10:829–843. doi: 10.1016/j.ymthe.2004.07.026. [DOI] [PubMed] [Google Scholar]
  71. Bo Li Z, Zhang J, Wagner KR. Inhibition of myostatin reverses muscle fibrosis through apoptosis. J Cell Sci. 2012;125(pt 17):3957–3965. doi: 10.1242/jcs.090365. [DOI] [PubMed] [Google Scholar]
  72. Adamo CM, Dai DF, Percival JM, et al. Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy. Proc Natl Acad Sci U S A. 2010;107:19079–19083. doi: 10.1073/pnas.1013077107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Percival JM, Whitehead NP, Adams ME, et al. Sildenafil reduces respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy. J Pathol. 2012;228:77–87. doi: 10.1002/path.4054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Martin EA, Barresi R, Byrne BJ, et al. Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy. Sci Transl Med. 2012;4:162ra155. doi: 10.1126/scitranslmed.3004327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Moyer AL, Wagner KR. Regeneration versus fibrosis in skeletal muscle. Curr Opin Rheumatol. 2011;23:568–573. doi: 10.1097/BOR.0b013e32834bac92. [DOI] [PubMed] [Google Scholar]
  76. Huebner KD, Jassal DS, Halevy O, et al. Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginone. Am J Physiol Heart Circ Physiol. 2008;294:H1550–H1561. doi: 10.1152/ajpheart.01253.2007. [DOI] [PubMed] [Google Scholar]
  77. Turgeman T, Hagai Y, Huebner K, et al. Prevention of muscle fibrosis and improvement in muscle performance in the mdx mouse by halofuginone. Neuromuscul Disord. 2008;18:857–868. doi: 10.1016/j.nmd.2008.06.386. [DOI] [PubMed] [Google Scholar]
  78. Dilworth FJ, Blais A. Epigenetic regulation of satellite cell activation during muscle regeneration. Stem Cell Res Ther. 2011;2:18. doi: 10.1186/scrt59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Botta A, Rinaldi F, Catalli C, et al. The CTG repeat expansion size correlates with the splicing defects observed in muscles from myotonic dystrophy type 1 patients. J Med Genet. 2008;45:639–646. doi: 10.1136/jmg.2008.058909. [DOI] [PubMed] [Google Scholar]
  80. Mankodi A, Urbinati CR, Yuan QP, et al. Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum Mol Genet. 2001;10:2165–2170. doi: 10.1093/hmg/10.19.2165. [DOI] [PubMed] [Google Scholar]
  81. Sistiaga A, Urreta I, Jodar M, et al. Cognitive/personality pattern and triplet expansion size in adult myotonic dystrophy type 1 (DM1): CTG repeats, cognition and personality in DM1. Psychol Med. 2010;40:487–495. doi: 10.1017/S0033291709990602. [DOI] [PubMed] [Google Scholar]
  82. Pincherle A, Patruno V, Raimondi P, et al. Sleep breathing disorders in 40 Italian patients with myotonic dystrophy type 1. Neuromuscul Disord. 2012;22:219–224. doi: 10.1016/j.nmd.2011.08.010. [DOI] [PubMed] [Google Scholar]
  83. Nelson DL, Orr HT, Warren ST. The unstable repeats—three evolving faces of neurological disease. Neuron. 2013;77:825–843. doi: 10.1016/j.neuron.2013.02.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Porensky PN, Burghes AH. Antisense oligonucleotides for the treatment of spinal muscular atrophy. Hum Gene Ther. 2013;24:489–498. doi: 10.1089/hum.2012.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Hilbert JE, Kissel JT, Luebbe EA, et al. If you build a rare disease registry, will they enroll and will they use it? Methods and data from the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD) Contemp Clin Trials. 2012;33:302–311. doi: 10.1016/j.cct.2011.11.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Thompson R, Schoser B, Monckton DG, et al. Patient Registries and Trial Readiness in Myotonic Dystrophy—TREAT-NMD/Marigold International Workshop Report. Neuromuscul Disord. 2009;19:860–866. doi: 10.1016/j.nmd.2009.08.009. [DOI] [PubMed] [Google Scholar]
  87. Griggs RC, Herr BE, Reha A, et al. Corticosteroids in Duchenne muscular dystrophy: major variations in practice. Muscle Nerve. 2013;48:27–31. doi: 10.1002/mus.23831. [DOI] [PubMed] [Google Scholar]
  88. Maddocks M, Gao W, Higginson IJ, Wilcock A. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane Database Syst Rev. 2013;1:CD009419. doi: 10.1002/14651858.CD009419.pub2. [DOI] [PubMed] [Google Scholar]
  89. Colson SS, Benchortane M, Tanant V, et al. Neuromuscular electrical stimulation training: a safe and effective treatment for facioscapulohumeral muscular dystrophy patients. Arch Phys Med Rehabil. 2010;91:697–702. doi: 10.1016/j.apmr.2010.01.019. [DOI] [PubMed] [Google Scholar]
  90. Eagle M. Report on the muscular dystrophy campaign workshop: exercise in neuromuscular diseases Newcastle, January 2002. Neuromuscul Disord. 2002;12:975–983. doi: 10.1016/s0960-8966(02)00136-0. [DOI] [PubMed] [Google Scholar]
  91. Lovering RM, Brooks SV. Eccentric exercise in aging and diseased skeletal muscle: good or bad? J Appl Physiol. doi: 10.1152/japplphysiol.00174.2013. 2013 Mar 7. doi: 10.1152/japplphysiol.00174.2013 [Epub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Voet NB, van der Kooi EL, Riphagen II, et al. Strength training and aerobic exercise training for muscle disease. Cochrane Database Syst Rev. 2013;7:CD003907. doi: 10.1002/14651858.CD003907.pub4. [DOI] [PubMed] [Google Scholar]
  93. Cup EH, Pieterse AJ, Ten Broek-Pastoor JM, et al. Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review. Arch Phys Med Rehabil. 2007;88:1452–1464. doi: 10.1016/j.apmr.2007.07.024. [DOI] [PubMed] [Google Scholar]
  94. Abresch RT, Carter GT, Han JJ, McDonald CM. Exercise in neuromuscular diseases. Phys Med Rehabil Clin N Am. 2012;23:653–673. doi: 10.1016/j.pmr.2012.06.001. [DOI] [PubMed] [Google Scholar]
  95. Anziska Y, Sternberg A. Exercise in neuromuscular disease. Muscle Nerve. 2013;48:3–20. doi: 10.1002/mus.23771. [DOI] [PubMed] [Google Scholar]
  96. Yuasa K, Sakamoto M, Miyagoe-Suzuki Y, et al. Adeno-associated virus vector-mediated gene transfer into dystrophin-deficient skeletal muscles evokes enhanced immune response against the transgene product. Gene Ther. 2002;9:1576–1588. doi: 10.1038/sj.gt.3301829. [DOI] [PubMed] [Google Scholar]
  97. Flanigan KM, Campbell K, Viollet L, Wang W, Gomez AM, Walker CM, Mendell JR. Anti-dystrophin T cell responses in duchenne muscular dystrophy: prevalence and a glucocorticoid treatment effect. Hum Gene Ther. 2013;24:797–806. doi: 10.1089/hum.2013.092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Bencze M, Negroni E, Vallese D, et al. Proinflammatory macrophages enhance the regenerative capacity of human myoblasts by modifying their kinetics of proliferation and differentiation. Mol Ther. 2012;20:2168–2179. doi: 10.1038/mt.2012.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Lesault PF, Theret M, Magnan M, et al. Macrophages improve survival, proliferation and migration of engrafted myogenic precursor cells into MDX skeletal muscle. PLoS ONE. 2012;7:e46698. doi: 10.1371/journal.pone.0046698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Karam R, Wengrod J, Gardner LB, Wilkinson MF. Regulation of nonsense-mediated mRNA decay: implications for physiology and disease. Biochim Biophys Acta. 2013;1829:624–633. doi: 10.1016/j.bbagrm.2013.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Keeling KM, Wang D, Dai Y, et al. Attenuation of nonsense-mediated mRNA decay enhances in vivo nonsense suppression. PLoS ONE. 2013;8:e60478. doi: 10.1371/journal.pone.0060478. [DOI] [PMC free article] [PubMed] [Google Scholar]

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