Skip to main content
SpringerLink
Log in
Book cover

Muscle Gene Therapy pp 727–743Cite as

Duchenne Muscular Dystrophy Exon-Skipping Trials

  • Chapter
  • First Online:

Abstract

This chapter demonstrates an alternative mode of molecular therapy with the goal of restoring the DMD gene to achieve clinical improvement using antisense oligonucleotides (AONs). Preclinical studies were successful in mdx mice showing persistent production of dystrophin at significant levels in large numbers of muscle fibers. These experimental studies led to the clinical introduction of a 2′-O-methyl-phosphorothioate oligonucleotide (2’OMePS) and a phosphorodiamidate morpholino oligonucleotide (PMO) to induce skipping of one or more exons, restoring the reading frame and allowing for the production of a BMD-like dystrophin. This chapter reviews the clinical trial experience, the side effect profiles, and the basis for FDA approval of the PMO product, introduced as eteplirsen. Following approval the product is identified as Exondys 51®. The results of the long-term, 36-month clinical trial are described. The findings included a change in the rate of decline and prolonged ambulation in DMD boys compared to natural history controls. Exondys 51™ represents the first drug other than deflazacort (Emflaza®) ever approved for DMD.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM (1987) Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50(3):509–517

    Article  CAS  Google Scholar 

  2. Wilton SD, Lloyd F, Carville K, Fletcher S, Honeyman K, Agrawal S, Kole R (1999) Specific removal of the nonsense mutation from the mdx dystrophin mRNA using antisense oligonucleotides. Neuromuscul Disord 9(5):330–338

    Article  CAS  Google Scholar 

  3. Lu QL, Mann CJ, Lou F, Bou-Gharios G, Morris GE, Xue SA, Fletcher S, Partridge TA, Wilton SD (2003) Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nat Med 9(8):1009–1014. https://doi.org/10.1038/nm897

    Article  CAS  PubMed  Google Scholar 

  4. Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van Deutekom J, van Ommen GJ, den Dunnen JT (2009) Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat 30(3):293–299. https://doi.org/10.1002/humu.20918

    Article  PubMed  Google Scholar 

  5. Frazier KS, Sobry C, Derr V, Adams MJ, Besten CD, De Kimpe S, Francis I, Gales TL, Haworth R, Maguire SR, Mirabile RC, Mullins D, Palate B, Doorten YP, Ridings JE, Scicchitano MS, Silvano J, Woodfine J (2014) Species-specific inflammatory responses as a primary component for the development of glomerular lesions in mice and monkeys following chronic administration of a second-generation antisense oligonucleotide. Toxicol Pathol 42(5):923–935. https://doi.org/10.1177/0192623313505781

    Article  CAS  PubMed  Google Scholar 

  6. Lee KW, Kim DS, Kwon HJ (2004) CG sequence- and phosphorothioate backbone modification-dependent activation of the NF-kappaB-responsive gene expression by CpG-oligodeoxynucleotides in human RPMI 8226 B cells. Mol Immunol 41(10):955–964. https://doi.org/10.1016/j.molimm.2004.06.022

    Article  CAS  PubMed  Google Scholar 

  7. van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A, Bremmer-Bout M, den Dunnen JT, Koop K, van der Kooi AJ, Goemans NM, de Kimpe SJ, Ekhart PF, Venneker EH, Platenburg GJ, Verschuuren JJ, van Ommen GJ (2007) Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med 357(26):2677–2686. https://doi.org/10.1056/NEJMoa073108

    Article  PubMed  Google Scholar 

  8. Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, Holling T, Janson AA, Platenburg GJ, Sipkens JA, Sitsen JM, Aartsma-Rus A, van Ommen GJ, Buyse G, Darin N, Verschuuren JJ, Campion GV, de Kimpe SJ, van Deutekom JC (2011) Systemic administration of PRO051 in Duchenne’s muscular dystrophy. N Engl J Med 364(16):1513–1522. https://doi.org/10.1056/NEJMoa1011367

    Article  CAS  PubMed  Google Scholar 

  9. Voit T, Topaloglu H, Straub V, Muntoni F, Deconinck N, Campion G, De Kimpe SJ, Eagle M, Guglieri M, Hood S, Liefaard L, Lourbakos A, Morgan A, Nakielny J, Quarcoo N, Ricotti V, Rolfe K, Servais L, Wardell C, Wilson R, Wright P, Kraus JE (2014) Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol 13(10):987–996. https://doi.org/10.1016/S1474-4422(14)70195-4

    Article  CAS  PubMed  Google Scholar 

  10. Carroll J (2013) Muscular dystrophy drug from GlaxoSmithKline, Prosensa fails PhI/II. Fierce Biotech

    Google Scholar 

  11. Flanigan KM, Voit T, Rosales XQ, Servais L, Kraus JE, Wardell C, Morgan A, Dorricott S, Nakielny J, Quarcoo N, Liefaard L, Drury T, Campion G, Wright P (2014) Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: results of a double-blind randomized clinical trial. Neuromuscul Disord 24(1):16–24. https://doi.org/10.1016/j.nmd.2013.09.004

    Article  PubMed  Google Scholar 

  12. Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P, Garralda ME, Rutherford M, McCulley C, Popplewell L, Graham IR, Dickson G, Wood MJ, Wells DJ, Wilton SD, Kole R, Straub V, Bushby K, Sewry C, Morgan JE, Muntoni F (2009) 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 8(10):918–928. https://doi.org/10.1016/S1474-4422(09)70211-X

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, Abbs S, Garralda ME, Bourke J, Wells DJ, Dickson G, Wood MJ, Wilton SD, Straub V, Kole R, Shrewsbury SB, Sewry C, Morgan JE, Bushby K, Muntoni F (2011) 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 378(9791):595–605. https://doi.org/10.1016/S0140-6736(11)60756-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Krieger CC, Bhasin N, Tewari M, Brown AE, Safer D, Sweeney HL, Discher DE (2010) Exon-skipped dystrophins for treatment of Duchenne muscular dystrophy: mass spectrometry mapping of most exons and cooperative domain designs based on single molecule mechanics. Cytoskeleton (Hoboken) 67(12):796–807. https://doi.org/10.1002/cm.20489

    Article  CAS  Google Scholar 

  15. Lai Y, Thomas GD, Yue Y, Yang HT, Li D, Long C, Judge L, Bostick B, Chamberlain JS, Terjung RL, Duan D (2009) Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy. J Clin Invest 119(3):624–635. https://doi.org/10.1172/JCI36612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Kota J, Malik V, Shontz K, Walker CM, Flanigan KM, Corridore M, Kean JR, Allen HD, Shilling C, Melia KR, Sazani P, Saoud JB, Kaye EM, Eteplirsen Study Group (2013) Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol 74(5):637–647. https://doi.org/10.1002/ana.23982

    Article  CAS  PubMed  Google Scholar 

  17. Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, Kaye EM, Mercuri E, Eteplirsen Study G, Telethon Foundation DMDIN (2016) Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol 79(2):257–271. https://doi.org/10.1002/ana.24555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Khirani S, Ramirez A, Aubertin G, Boule M, Chemouny C, Forin V, Fauroux B (2014) Respiratory muscle decline in Duchenne muscular dystrophy. Pediatr Pulmonol 49(5):473–481. https://doi.org/10.1002/ppul.22847

    Article  PubMed  Google Scholar 

  19. Mayer OH, Finkel RS, Rummey C, Benton MJ, Glanzman AM, Flickinger J, Lindstrom BM, Meier T (2015) Characterization of pulmonary function in Duchenne muscular dystrophy. Pediatr Pulmonol 50(5):487–494. https://doi.org/10.1002/ppul.23172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Goemans N, van den Hauwe M, Wilson R, van Impe A, Klingels K, Buyse G (2013) Ambulatory capacity and disease progression as measured by the 6-minute-walk-distance in Duchenne muscular dystrophy subjects on daily corticosteroids. Neuromuscul Disord 23(8):618–623. https://doi.org/10.1016/j.nmd.2013.05.006

    Article  PubMed  Google Scholar 

  21. Pane M, Mazzone ES, Sivo S, Sormani MP, Messina S, D’Amico A, Carlesi A, Vita G, Fanelli L, Berardinelli A, Torrente Y, Lanzillotta V, Viggiano E, D’Ambrosio P, Cavallaro F, Frosini S, Barp A, Bonfiglio S, Scalise R, De Sanctis R, Rolle E, Graziano A, Magri F, Palermo C, Rossi F, Donati MA, Sacchini M, Arnoldi MT, Baranello G, Mongini T, Pini A, Battini R, Pegoraro E, Previtali S, Bruno C, Politano L, Comi GP, Bertini E, Mercuri E (2014) Long term natural history data in ambulant boys with Duchenne muscular dystrophy: 36-month changes. PLoS One 9(10):e108205. https://doi.org/10.1371/journal.pone.0108205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. McDonald CM, Henricson EK, Abresch RT, Florence J, Eagle M, Gappmaier E, Glanzman AM, Group PG-DS, Spiegel R, Barth J, Elfring G, Reha A, Peltz SW (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(3):357–368. https://doi.org/10.1002/mus.23905

    Article  PubMed  PubMed Central  Google Scholar 

  23. Henricson EK, Abresch RT, Cnaan A, Hu F, Duong T, Arrieta A, Han J, Escolar DM, Florence JM, Clemens PR, Hoffman EP, McDonald CM, Investigators C (2013) The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve 48(1):55–67. https://doi.org/10.1002/mus.23808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Unger EF, Califf RM (2017) Regarding “Eteplirsen for the treatment of Duchenne muscular dystrophy”. Ann Neurol 81(1):162–164. https://doi.org/10.1002/ana.24842

    Article  PubMed  Google Scholar 

  25. Mendell JR (2017) Reply to letter to the editor. Mol Ther 25(10):2238–2240. https://doi.org/10.1016/j.ymthe.2017.09.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Muntoni F, Bushby KD, van Ommen G (2008) 149th ENMC International Workshop and 1st TREAT-NMD Workshop on: “planning phase i/ii clinical trials using systemically delivered antisense oligonucleotides in Duchenne muscular dystrophy”. Neuromuscul Disord 18(3):268–275. https://doi.org/10.1016/j.nmd.2007.11.010

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Nationwide Children’s Hospital and Research Institute, The Ohio State University, Columbus, OH, USA

    Jerry R. Mendell, Zarife Sahenk & Louise R. Rodino-Klapac

  2. Department of Neurology, Nationwide Children’s Hospital and Research Institute, The Ohio State University, Columbus, OH, USA

    Jerry R. Mendell & Zarife Sahenk

  3. Vice President Gene Therapy, Sarepta Therapeutics, Columbus, OH, USA

    Louise R. Rodino-Klapac

Authors
  1. Jerry R. Mendell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zarife Sahenk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Louise R. Rodino-Klapac
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jerry R. Mendell .

Editor information

Editors and Affiliations

  1. Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA, Department of Biomedical Sciences College of Veterinary Medicine, University of Missouri, Columbia, MO, USA; Department of Bioengineering, University of Missouri, Columbia, MO, USA

    Dongsheng Duan

  2. Department of Pediatrics Nationwide Children’s Hospital and Research Institute, Department of Neurology Nationwide Children’s Hospital and Research Institute, The Ohio State University, Columbus, OH, USA

    Jerry R. Mendell

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mendell, J.R., Sahenk, Z., Rodino-Klapac, L.R. (2019). Duchenne Muscular Dystrophy Exon-Skipping Trials. In: Duan, D., Mendell, J. (eds) Muscle Gene Therapy. Springer, Cham. https://doi.org/10.1007/978-3-030-03095-7_42

Download citation

Publish with us

Policies and ethics

Search

Navigation