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An Overview of Recent Therapeutics Advances for Duchenne Muscular Dystrophy

  • Jean K. Mah
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1687)

Abstract

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. Mutations of the DMD gene destabilize the dystrophin associated glycoprotein complex in the sarcolemma. Ongoing mechanical stress leads to unregulated influx of calcium ions into the sarcoplasm, with activation of proteases, release of proinflammatory cytokines, and mitochondrial dysfunction. Cumulative damage and reparative failure leads to progressive muscle necrosis, fibrosis, and fatty replacement. Although there is presently no cure for DMD, scientific advances have led to many potential disease-modifying treatments, including dystrophin replacement therapies, upregulation of compensatory proteins, anti-inflammatory agents, and other cellular targets. Recently approved therapies include ataluren for stop codon read-through and eteplirsen for exon 51 skipping of eligible individuals. The purpose of this chapter is to summarize the clinical features of DMD, to describe current outcome measures used in clinical studies, and to highlight new emerging therapies for affected individuals.

Key words

Duchenne muscular dystrophy Outcome measures Disease-modifying treatments 

References

  1. 1.
    Emery AE, Emery ML (1993) Edward Meryon (1809-1880) and muscular dystrophy. J Med Genet 30:506–511CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Hoffman EP, Brown RH, Kunkel LM (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51:919–928CrossRefPubMedGoogle Scholar
  3. 3.
    Emery AE (1991) Population frequencies of inherited neuromuscular diseases – a world survey. Neuromuscul Disord 1:19–29CrossRefPubMedGoogle Scholar
  4. 4.
    Mah JK, Korngut L, Dykeman J, Day L, Pringsheim T, Jette N (2014) A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscul Disord 24:482–491CrossRefPubMedGoogle Scholar
  5. 5.
    Monaco AP, Bertelson CJ, Liechti-Gallati S, Moser H, Kunkel LM (1988) An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 2:90–95CrossRefPubMedGoogle Scholar
  6. 6.
    Aartsma-Rus A, Van Deutekom JC, Fokkema IF, Van Ommen GJ, Den Dunnen JT (2006) Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle Nerve 34:135–144CrossRefPubMedGoogle Scholar
  7. 7.
    Bushby K, Finkel R, Birnkrant DJ et al (2010) Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 9:77–93CrossRefPubMedGoogle Scholar
  8. 8.
    Mah JK, Selby K, Campbell C et al (2011) A population-based study of dystrophin mutations in Canada. Can J Neurol Sci 38:465–474CrossRefPubMedGoogle Scholar
  9. 9.
    McDonald CM, Henricson EK, Abresch RT et al (2013) The cooperative international neuromuscular research group Duchenne natural history study--a longitudinal investigation in the era of glucocorticoid therapy: design of protocol and the methods used. Muscle Nerve 48:32–54CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bushby K, Connor E (2011) Clinical outcome measures for trials in Duchenne muscular dystrophy: report from international working group meetings. Clin Investig (Lond) 1:1217–1235CrossRefGoogle Scholar
  11. 11.
    Henricson E, Abresch R, Han JJ et al (2013) The 6-minute walk test and person-reported outcomes in boys with Duchenne muscular dystrophy and typically developing controls: longitudinal comparisons and clinically-meaningful changes over one year. PLoS Curr 5. doi: 10.1371/currents.md.9e17658b007eb79fcd6f723089f79e06
  12. 12.
    Mazzone ES, Messina S, Vasco G et al (2009) Reliability of the north star ambulatory assessment in a multicentric setting. Neuromuscul Disord 19:458–461CrossRefPubMedGoogle Scholar
  13. 13.
    Escolar DM, Hache LP, Clemens PR et al (2011) Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy. Neurology 77:444–452CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    McDonald CM, Henricson EK, Han JJ et al (2010) The 6-minute walk test in Duchenne/Becker muscular dystrophy: longitudinal observations. Muscle Nerve 42:966–974CrossRefPubMedGoogle Scholar
  15. 15.
    McDonald CM, Henricson EK, Abresch RT et al (2013) The 6-minute walk test and other clinical endpoints in duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study. Muscle Nerve 48:357–368CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    McDonald CM, Henricson EK, Abresch RT et al (2013) The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. Muscle Nerve 48:343–356CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Pane M, Mazzone ES, Sivo S et al (2014) Long term natural history data in ambulant boys with Duchenne muscular dystrophy: 36-month changes. PLoS One 9:e108205CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Mazzone E, Vasco G, Sormani MP et al (2011) Functional changes in Duchenne muscular dystrophy: a 12-month longitudinal cohort study. Neurology 77:250–256CrossRefPubMedGoogle Scholar
  19. 19.
    Mazzone ES, Pane M, Sormani MP et al (2013) 24 month longitudinal data in ambulant boys with Duchenne muscular dystrophy. PLoS One 8:e52512CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Steffensen B, Hyde S, Lyager S, Mattsson E (2001) Validity of the EK scale: a functional assessment of non-ambulatory individuals with Duchenne muscular dystrophy or spinal muscular atrophy. Physiother Res Int 6:119–134CrossRefPubMedGoogle Scholar
  21. 21.
    Mercuri E, McDonald C, Mayhew A et al (2012) International workshop on assessment of upper limb function in Duchenne muscular dystrophy: Rome, 15-16 February 2012. Neuromuscul Disord 22:1025–1028CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mayhew A, Mazzone ES, Eagle M et al (2013) Development of the performance of the upper limb module for Duchenne muscular dystrophy. Dev Med Child Neurol 55:1038–1045CrossRefPubMedGoogle Scholar
  23. 23.
    Pane M, Mazzone ES, Sivo S et al (2014) The 6 minute walk test and performance of upper limb in ambulant duchenne muscular dystrophy boys. PLoS Curr 6. doi: 10.1371/currents.md.a93d9904d57dcb08936f2ea89bca6fe6
  24. 24.
    Arechavala-Gomeza V, Kinali M, Feng L et al (2010) Revertant fibres and dystrophin traces in Duchenne muscular dystrophy: implication for clinical trials. Neuromuscul Disord 20:295–301CrossRefPubMedGoogle Scholar
  25. 25.
    Hathout Y, Brody E, Clemens PR et al (2015) Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 112:7153–7158CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Willcocks RJ, Rooney WD, Triplett WT et al (2016) Multicenter prospective longitudinal study of magnetic resonance biomarkers in a large duchenne muscular dystrophy cohort. Ann Neurol 79:535–547CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Mendell JR, Rodino-Klapac LR, Sahenk Z et al (2013) Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol 74:637–647CrossRefPubMedGoogle Scholar
  28. 28.
    Mendell JR, Goemans N, Lowes LP et al (2016) Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol 79:257–271CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Aartsma-Rus A, Ginjaar IB, Bushby K (2016) The importance of genetic diagnosis for Duchenne muscular dystrophy. J Med Genet 53:145–151CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Finkel RS, Flanigan KM, Wong B et al (2013) Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy. PLoS One 8:e81302CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bushby K, Finkel R, Wong B et al (2014) Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve 50:477–487CrossRefPubMedGoogle Scholar
  32. 32.
    Chicoine LG, Rodino-Klapac LR, Shao G et al (2014) Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin α2 surrogates. Mol Ther 22:713–724CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Okada T, Takeda S (2013) Current challenges and future directions in recombinant AAV-mediated gene therapy of Duchenne muscular dystrophy. Pharmaceuticals (Basel) 6:813–836CrossRefPubMedCentralGoogle Scholar
  34. 34.
    Briggs D, Morgan JE (2013) Recent progress in satellite cell/myoblast engraftment – relevance for therapy. FEBS J 280:4281–4293CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ito M, Ehara Y, Li J, Inada K, Ohno K (2016) Protein-anchoring therapy of Biglycan for mdx mouse model of Duchenne muscular dystrophy. Hum Gene Ther. doi: 10.1089/hum.2015.088
  36. 36.
    Guiraud S, Squire SE, Edwards B et al (2015) Second-generation compound for the modulation of utrophin in the therapy of DMD. Hum Mol Genet 24:4212–4224CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Wagner KR, McPherron AC, Winik N, Lee SJ (2002) Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann Neurol 52:832–836CrossRefPubMedGoogle Scholar
  38. 38.
    Bogdanovich S, Krag TO, Barton ER et al (2002) Functional improvement of dystrophic muscle by myostatin blockade. Nature 420:418–421CrossRefPubMedGoogle Scholar
  39. 39.
    Andreetta F, Bernasconi P, Baggi F et al (2006) Immunomodulation of TGF-beta 1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: implications for antifibrotic therapy. J Neuroimmunol 175:77–86CrossRefPubMedGoogle Scholar
  40. 40.
    Consalvi S, Mozzetta C, Bettica P et al (2013) Preclinical studies in the mdx mouse model of duchenne muscular dystrophy with the histone deacetylase inhibitor givinostat. Mol Med 19:79–87CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Bettica P, Petrini S, D'Oria V et al (2016) Histological effects of givinostat in boys with Duchenne muscular dystrophy. Neuromuscul Disord 26:643–649CrossRefPubMedGoogle Scholar
  42. 42.
    Miyatake S, Shimizu-Motohashi Y, Takeda S, Aoki Y (2016) Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors. Drug Des Devel Ther 10:2745–2758CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Bello L, Gordish-Dressman H, Morgenroth LP et al (2015) Prednisone/prednisolone and deflazacort regimens in the CINRG Duchenne natural history study. Neurology 85:1048–1055CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Heier CR, Damsker JM, Yu Q et al (2013) VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects. EMBO Mol Med 5:1569–1585CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Gao QQ, McNally EM (2015) The Dystrophin complex: structure, function, and implications for therapy. Compr Physiol 5:1223–1239CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Hernández-Ochoa EO, Pratt SJ, Lovering RM, Schneider MF (2015) Critical role of intracellular RyR1 calcium release channels in skeletal muscle function and disease. Front Physiol 6:420PubMedGoogle Scholar
  47. 47.
    Bowman CL, Gottlieb PA, Suchyna TM, Murphy YK, Sachs F (2007) Mechanosensitive ion channels and the peptide inhibitor GsMTx-4: history, properties, mechanisms and pharmacology. Toxicon 49:249–270CrossRefPubMedGoogle Scholar
  48. 48.
    Bushby K, Finkel R, Birnkrant DJ et al (2010) Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol 9:177–189CrossRefPubMedGoogle Scholar
  49. 49.
    McNally EM, Kaltman JR, Benson DW et al (2015) Contemporary cardiac issues in Duchenne muscular dystrophy. Working Group of the National Heart, lung, and blood institute in collaboration with Parent Project Muscular Dystrophy. Circulation 131:1590–1515CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Birnkrant DJ, Bushby KM, Amin RS et al (2010) The respiratory management of patients with Duchenne muscular dystrophy: a DMD care considerations working group specialty article. Pediatr Pulmonol 45:739–748CrossRefPubMedGoogle Scholar
  51. 51.
    Morgenroth VH, Hache LP, Clemens PR (2012) Insights into bone health in Duchenne muscular dystrophy. Bonekey Rep 1:9CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  1. 1.Department of Paediatrics and Clinical Neurosciences, Cumming School of MedicineUniversity of CalgaryCalgaryCanada

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