Current Status of Antisense Oligonucleotide-Based Therapy in Neuromuscular Disorders

A Correction to this article was published on 04 August 2020

This article has been updated


Neuromuscular disorders include a wide range of diseases affecting the peripheral nervous system, which are primarily characterized by progressive muscle weakness and wasting. While there were no effective therapies until recently, several therapeutic approaches have advanced to clinical trials in the past few years. Among these, the antisense technology aiming at modifying RNA processing and function has remarkably progressed and a few antisense oligonucleotides (ASOs) have now been approved. Despite these recent clinical successes, several ASOs have also failed and clinical programs have been suspended, in most cases when the route of administration was systemic, highlighting the existing challenges notably with respect to effective ASO delivery. In this review we summarize the recent advances and current status of antisense based-therapies for neuromuscular disorders, using successful as well as unsuccessful examples to highlight the variability of outcomes depending on the target tissue and route of administration. We describe the different ASO-mediated therapeutic approaches, including splice-switching applications, steric-blocking strategies and targeted gene knock-down mediated by ribonuclease H recruitment. In this overview, we discuss the merits and challenges of the current ASO technology, and discuss the future of ASO development.

This is a preview of subscription content, access via your institution.

Fig. 1

Change history

  • 04 August 2020

    The second author, which currently reads as: Adeline Vulin-Chaffiol.


  1. 1.

    Kaur H, Wengel J, Maiti S. LNA-modified oligonucleotides effectively drive intramolecular-stable hairpin to intermolecular-duplex state. Biochem Biophys Res Commun. 2007;352:118–22.

    CAS  PubMed  Google Scholar 

  2. 2.

    Griepenburg JC, Rapp TL, Carroll PJ, Eberwine J, Dmochowski IJ. Ruthenium-caged antisense morpholinos for regulating gene expression in zebrafish embryos. Chem Sci. 2015;6:2342–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Gilar M, Belenky A, Smisek DL, Bourque A, Cohen AS. Kinetics of phosphorothioate oligonucleotide metabolism in biological fluids. Nucleic Acids Res. 1997;25:3615–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Zamecnik PC, Stephenson ML. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci USA. 1978;75:280–4.

    CAS  PubMed  Google Scholar 

  5. 5.

    Schoch KM, Miller TM. Antisense oligonucleotides: translation from mouse models to human neurodegenerative diseases. Neuron. 2017;94:1056–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Wickstrom E. Oligodeoxynucleotide stability in subcellular extracts and culture media. J Biochem Biophys Methods. 1986;13:97–102.

    CAS  PubMed  Google Scholar 

  7. 7.

    Gaus HJ, Gupta R, Chappell AE, Østergaard ME, Swayze EE, Seth PP. Characterization of the interactions of chemically-modified therapeutic nucleic acids with plasma proteins using a fluorescence polarization assay. Nucleic Acids Res. 2019;47:1110–22.

    CAS  PubMed  Google Scholar 

  8. 8.

    Crooke ST, Wang S, Vickers TA, Shen W, Liang X-H. Cellular uptake and trafficking of antisense oligonucleotides. Nat Biotechnol. 2017;35:230–7.

    CAS  PubMed  Google Scholar 

  9. 9.

    Iannitti T, Morales-Medina JC, Palmieri B. Phosphorothioate oligonucleotides: effectiveness and toxicity. Curr Drug Targets. 2014;15:663–73.

    CAS  PubMed  Google Scholar 

  10. 10.

    Crooke ST, Baker BF, Witztum JL, Kwoh TJ, Pham NC, Salgado N, et al. The effects of 2′-O-methoxyethyl containing antisense oligonucleotides on platelets in human clinical trials. Nucleic Acid Ther. 2017;27:121–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Senn JJ, Burel S, Henry SP. Non-CpG-containing antisense 2′-methoxyethyl oligonucleotides activate a proinflammatory response independent of Toll-like receptor 9 or myeloid differentiation factor 88. J Pharmacol Exp Ther. 2005;314:972–9.

    CAS  PubMed  Google Scholar 

  12. 12.

    Henry SP, Beattie G, Yeh G, Chappel A, Giclas P, Mortari A, et al. Complement activation is responsible for acute toxicities in rhesus monkeys treated with a phosphorothioate oligodeoxynucleotide. Int Immunopharmacol. 2002;2:1657–66.

    CAS  PubMed  Google Scholar 

  13. 13.

    Sheehan JP, Phan TM. Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex by an allosteric mechanism. Biochemistry. 2001;40:4980–9.

    CAS  PubMed  Google Scholar 

  14. 14.

    Eckstein F. Phosphorothioates, essential components of therapeutic oligonucleotides. Nucleic Acid Ther. 2014;24:374–87.

    CAS  PubMed  Google Scholar 

  15. 15.

    Goyenvalle A, Leumann C, Garcia L. Therapeutic Potential of Tricyclo-DNA antisense oligonucleotides. J Neuromuscul Dis. 2016;3:157–67.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Henry S, Stecker K, Brooks D, Monteith D, Conklin B, Bennett CF. Chemically modified oligonucleotides exhibit decreased immune stimulation in mice. J Pharmacol Exp Ther. 2000;292:468–79.

    CAS  PubMed  Google Scholar 

  17. 17.

    Summerton J, Weller D. Morpholino antisense oligomers: design, preparation, and properties. Antisense Nucleic Acid Drug Dev. 1997;7:187–95.

    CAS  PubMed  Google Scholar 

  18. 18.

    Hagedorn PH, Persson R, Funder ED, Albæk N, Diemer SL, Hansen DJ, et al. Locked nucleic acid: modality, diversity, and drug discovery. Drug Discov Today. 2017.

    Article  PubMed  Google Scholar 

  19. 19.

    Seth PP, Siwkowski A, Allerson CR, Vasquez G, Lee S, Prakash TP, et al. Design, synthesis and evaluation of constrained methoxyethyl (cMOE) and constrained ethyl (cEt) nucleoside analogs. Nucleic Acids Symp Ser (Oxf). 2008.

    Article  Google Scholar 

  20. 20.

    Gupta A, Mishra A, Puri N. Peptide nucleic acids: advanced tools for biomedical applications. J Biotechnol. 2017;259:148–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Crooke ST, Witztum JL, Bennett CF, Baker BF. RNA-targeted therapeutics. Cell Metab. 2019;29:501.

    CAS  PubMed  Google Scholar 

  22. 22.

    Bennett CF. Therapeutic antisense oligonucleotides are coming of age. Annu Rev Med. 2019;70:307–21.

    CAS  PubMed  Google Scholar 

  23. 23.

    Crooke ST. Molecular mechanisms of antisense oligonucleotides. Nucleic Acid Ther. 2017;27:70–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Godfrey C, Desviat LR, Smedsrød B, Piétri-Rouxel F, Denti MA, Disterer P, et al. Delivery is key: lessons learnt from developing splice-switching antisense therapies. EMBO Mol Med. 2017;9:545–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Mah JK, Korngut L, Dykeman J, Day L, Pringsheim T, Jette N. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscul Disord. 2014;24:482–91.

    PubMed  Google Scholar 

  26. 26.

    Arechavala-Gomeza V, Kinali M, Feng L, Guglieri M, Edge G, Main M, et al. Revertant fibers and dystrophin traces in Duchenne muscular dystrophy: implication for clinical trials. Neuromuscul Disord. 2010;20:295–301.

    PubMed  Google Scholar 

  27. 27.

    Lu QL, Morris GE, Wilton SD, Ly T, Artem’yeva OV, Strong P, et al. Massive idiosyncratic exon skipping corrects the nonsense mutation in dystrophic mouse muscle and produces functional revertant fibers by clonal expansion. J Cell Biol. 2000;148:985–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van Deutekom J, van Ommen GJ, et al. Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat. 2009;30:293–9.

    PubMed  Google Scholar 

  29. 29.

    Takeshima Y, Yagi M, Wada H, Ishibashi K, Nishiyama A, Kakumoto M, et al. Intravenous infusion of an antisense oligonucleotide results in exon skipping in muscle dystrophin mRNA of Duchenne muscular dystrophy. Pediatr Res. 2006;59:690–4.

    CAS  PubMed  Google Scholar 

  30. 30.

    Lu QL, Mann CJ, Lou F, Bou-Gharios G, Morris GE, Xue SA, et al. Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nat Med. 2003;9:1009–14.

    CAS  PubMed  Google Scholar 

  31. 31.

    Van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A, Bremmer-Bout M, et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med. 2007;357:2677–86.

    PubMed  Google Scholar 

  32. 32.

    Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, et al. Systemic administration of PRO051 in Duchenne’s muscular dystrophy. N Engl J Med. 2011;364:1513–22.

    CAS  PubMed  Google Scholar 

  33. 33.

    Goemans NM, Tulinius M, van den Hauwe M, Kroksmark A-K, Buyse G, Wilson RJ, et al. Long-term efficacy, safety, and pharmacokinetics of drisapersen in duchenne muscular dystrophy: results from an open-label extension study. PLoS One. 2016;11:e0161955.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Goemans N, Mercuri E, Belousova E, Komaki H, Dubrovsky A, McDonald CM, et al. A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy. Neuromuscul Disord. 2018;28:4–15.

    PubMed  Google Scholar 

  35. 35.

    Alter J, Lou F, Rabinowitz A, Yin H, Rosenfeld J, Wilton SD, et al. Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat Med. 2006;12:175–7.

    CAS  PubMed  Google Scholar 

  36. 36.

    Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, 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;8:918–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy: eteplirsen for DMD. Ann Neurol. 2013;74:637–47.

    CAS  PubMed  Google Scholar 

  39. 39.

    Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy: eteplirsen in DMD. Ann Neurol. 2016;79:257–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Aartsma-Rus A, Goemans N. A sequel to the eteplirsen saga: eteplirsen is approved in the united states but was not approved in Europe. Nucleic Acid Ther. 2019;29:13–5.

    CAS  PubMed  Google Scholar 

  41. 41.

    Alfano LN, Charleston JS, Connolly AM, Cripe L, Donoghue C, Dracker R, et al. Long-term treatment with eteplirsen in nonambulatory patients with Duchenne muscular dystrophy. Medicine (Baltimore). 2019;98:e15858.

    Google Scholar 

  42. 42.

    Carver MP, Charleston JS, Shanks C, Zhang J, Mense M, Sharma AK, et al. Toxicological characterization of exon skipping phosphorodiamidate morpholino oligomers (PMOs) in non-human primates. J Neuromuscul Dis. 2016;3:381–93.

    PubMed  Google Scholar 

  43. 43.

    Frank DE, Schnell FJ, Akana C, El-Husayni SH, Desjardins CA, Morgan J, et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology. 2020;94:e2270–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Heo Y-A. Golodirsen: first approval. Drugs. 2020;80:329–33.

    PubMed  Google Scholar 

  45. 45.

    Komaki H, Nagata T, Saito T, Masuda S, Takeshita E, Sasaki M, et al. Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy. Sci Transl Med. 2018;10(437):eaan0713.

    PubMed  Google Scholar 

  46. 46.

    Roshmi RR, Yokota T. Viltolarsen for the treatment of Duchenne muscular dystrophy. Drugs Today. 2019;55:627–39.

    CAS  PubMed  Google Scholar 

  47. 47.

    Aartsma-Rus A, Morgan J, Lonkar P, Neubert H, Owens J, Binks M, et al. Report of a TREAT-NMD/World Duchenne Organisation Meeting on dystrophin quantification methodology. J Neuromuscul Dis. 2019;6:147–59.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Wave Life Sciences Announces Suvodirsen Phase 1 Safety and Tolerability Data and Phase 2/3 Clinical Trial Design. Wave Life Sciences. 2020. Accessed May 2020.

  49. 49.

    Lee T, Awano H, Yagi M, Matsumoto M, Watanabe N, Goda R, et al. 2′-O-methyl RNA/ethylene-bridged nucleic acid chimera antisense oligonucleotides to induce dystrophin exon 45 skipping. Genes (Basel). 2017;8:67.

    Google Scholar 

  50. 50.

    DAIICHI SANKYO COMPANY (2018). Daiichi Sankyo Announces Phase 1/2 Clinical Trial Results for DS-5141 (Therapeutic Agent for Duchenne Muscular Dystrophy) in Japanat

  51. 51.

    Gait MJ, Arzumanov AA, McClorey G, Godfrey C, Betts C, Hammond S, et al. Cell-Penetrating peptide conjugates of steric blocking oligonucleotides as therapeutics for neuromuscular diseases from a historical perspective to current prospects of treatment. Nucleic Acid Ther. 2019;29:1–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Moulton HM, Moulton JD. Morpholinos and their peptide conjugates: therapeutic promise and challenge for Duchenne muscular dystrophy. Biochim Biophys Acta.

  53. 53.

    Goyenvalle A, Griffith G, Babbs A, El Andaloussi S, Ezzat K, Avril A, et al. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat Med. 2015;21:270–5.

    CAS  PubMed  Google Scholar 

  54. 54.

    Relizani K, Griffith G, Echevarría L, Zarrouki F, Facchinetti P, Vaillend C, et al. Efficacy and safety profile of tricyclo-DNA antisense oligonucleotides in duchenne muscular dystrophy mouse model. Mol Ther Nucleic Acids. 2017;8:144–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Goyenvalle A, Vulin A, Fougerousse F, Leturcq F, Kaplan JC, Garcia L, et al. Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping. Science. 2004;306:1796–9.

    CAS  PubMed  Google Scholar 

  56. 56.

    Vulin A, Barthelemy I, Goyenvalle A, Thibaud JL, Beley C, Griffith G, et al. Muscle function recovery in golden retriever muscular dystrophy after AAV1-U7 exon skipping. Mol Ther. 2012;20:2120–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Wein N, Vulin A, Falzarano MS, Szigyarto CA-K, Maiti B, Findlay A, et al. Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Nat Med. 2014;20:992–1000.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Verhaart IEC, Robertson A, Wilson IJ, Aartsma-Rus A, Cameron S, Jones CC, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy—a literature review. Orphanet J Rare Dis. 2017;12:124.

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Calucho M, Bernal S, Alías L, March F, Venceslá A, Rodríguez-Álvarez FJ, et al. Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul Disord. 2018;28:208–15.

    PubMed  Google Scholar 

  60. 60.

    Scholl R, Marquis J, Meyer K, Schümperli D. Spinal muscular atrophy: position and functional importance of the branch site preceding SMN exon 7. RNA Biol. 2007;4:34–7.

    CAS  PubMed  Google Scholar 

  61. 61.

    Singh RN, Singh NN. Mechanism of splicing regulation of spinal muscular atrophy genes. Adv Neurobiol. 2018;20:31–61.

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Singh NK, Singh NN, Androphy EJ, Singh RN. Splicing of a critical exon of human survival motor neuron is regulated by a unique silencer element located in the last intron. Mol Cell Biol. 2006;26:1333–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, et al. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 2010;24:1634–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett CF, et al. Peripheral SMN restoration is essential for long-term rescue of a severe SMA mouse model. Nature. 2011;478:123–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC, et al. Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy. Neurology. 2016;86:890–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388:3017–26.

    CAS  PubMed  Google Scholar 

  67. 67.

    Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscular Disord.

  68. 68.

    Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018;378:625–35.

    CAS  PubMed  Google Scholar 

  69. 69.

    Darras BT, Chiriboga CA, Iannaccone ST, Swoboda KJ, Montes J, Mignon L, et al. Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies. Neurology. 2019;92:e2492–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Meylemans A, De Bleecker J. Current evidence for treatment with nusinersen for spinal muscular atrophy: a systematic review. Acta Neurol Belg. 2019;119:523–33.

    PubMed  Google Scholar 

  71. 71.

    Shababi M, Lorson CL, Rudnik-Schöneborn SS. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat. 2014;224:15–28.

    CAS  PubMed  Google Scholar 

  72. 72.

    Bortolani S, Stura G, Ventilii G, Vercelli L, Rolle E, Ricci F, et al. Intrathecal administration of nusinersen in adult and adolescent patients with spinal muscular atrophy and scoliosis: transforaminal versus conventional approach. Neuromuscul Disord. 2019;29:742–6.

    PubMed  Google Scholar 

  73. 73.

    Cordts I, Lingor P, Friedrich B, Pernpeintner V, Zimmer C, Deschauer M et al. Intrathecal nusinersen administration in adult spinal muscular atrophy patients with complex spinal anatomy. Ther Adv Neurol Disord. 2020;13.

  74. 74.

    Strauss KA, Carson VJ, Brigatti KW, Young M, Robinson DL, Hendrickson C, et al. Preliminary safety and tolerability of a novel subcutaneous intrathecal catheter system for repeated outpatient dosing of nusinersen to children and adults with spinal muscular atrophy. J Pediatr Orthop. 2018;38:e610–7.

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Hammond SM, Hazell G, Shabanpoor F, Saleh AF, Bowerman M, Sleigh JN, et al. Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Proc Natl Acad Sci USA. 2016;113:10962–7.

    CAS  PubMed  Google Scholar 

  76. 76.

    Robin V, Griffith G, Carter J-PL, Leumann CJ, Garcia L, Goyenvalle A. Efficient SMN rescue following subcutaneous tricyclo-DNA antisense oligonucleotide treatment. Mol Ther Nucleic Acids. 2017;7:81–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Ramdas S, Servais L. New treatments in spinal muscular atrophy: an overview of currently available data. Expert Opin Pharmacother. 2020;21:307–15.

    CAS  PubMed  Google Scholar 

  78. 78.

    Harper PS. Myotonic dystrophy. Oxford: Oxford University Press; 2009. p. 106.

    Google Scholar 

  79. 79.

    Overby SJ, Cerro-Herreros E, Llamusi B, Artero R. RNA-mediated therapies in myotonic dystrophy. Drug Discov Today. 2018;23:2013–22.

    CAS  PubMed  Google Scholar 

  80. 80.

    Wheeler TM, Lueck JD, Swanson MS, Dirksen RT, Thornton CA. Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy. J Clin Investig. 2007.

    Article  PubMed  Google Scholar 

  81. 81.

    Wheeler TM, Sobczak K, Lueck JD, Osborne RJ, Lin X, Dirksen RT, et al. Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science. 2009;325:336–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Lee JE, Bennett CF, Cooper TA. RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1. Proc Natl Acad Sci USA. 2012;109:4221–6.

    CAS  PubMed  Google Scholar 

  83. 83.

    Wheeler TM, Leger AJ, Pandey SK, MacLeod AR, Nakamori M, Cheng SH, et al. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature. 2012;488:111–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Seth PP, Siwkowski A, Allerson CR, Vasquez G, Lee S, Prakash TP, et al. Short antisense oligonucleotides with novel 2–4′ conformationaly restricted nucleoside analogues show improved potency without increased toxicity in animals. J Med Chem. 2009;52:10–3.

    CAS  PubMed  Google Scholar 

  85. 85.

    Pandey SK, Wheeler TM, Justice SL, Kim A, Younis HS, Gattis D, et al. Identification and characterization of modified antisense oligonucleotides targeting DMPK in mice and nonhuman primates for the treatment of myotonic dystrophy type 1. J Pharmacol Exp Ther. 2015;355:310–21.

    CAS  Google Scholar 

  86. 86.

    Jauvin D, Chrétien J, Pandey SK, Martineau L, Revillod L, Bassez G, et al. Targeting DMPK with antisense oligonucleotide improves muscle strength in myotonic dystrophy type 1 mice. Mol Ther Nucleic Acids. 2017;7:465–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    González-Barriga A, Kranzen J, Croes HJE, Bijl S, van den Broek WJAA, van Kessel IDG, et al. Cell membrane integrity in myotonic dystrophy type 1: implications for therapy. PLoS One. 2015;10:e0121556.

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Prakash TP, Mullick AE, Lee RG, Yu J, Yeh ST, Low A, et al. Fatty acid conjugation enhances potency of antisense oligonucleotides in muscle. Nucleic Acids Res. 2019;47:6029–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Østergaard ME, Jackson M, Low AE, Chappell AG, Lee R, Peralta RQ, et al. Conjugation of hydrophobic moieties enhances potency of antisense oligonucleotides in the muscle of rodents and non-human primates. Nucleic Acids Res. 2019;47:6045–58.

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Klein AF, Varela MA, Arandel L, Holland A, Naouar N, Arzumanov A, et al. Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice. J. Clin. Investig. 2019;129:4739–44.

    CAS  PubMed  Google Scholar 

  91. 91.

    Talbott EO, Malek AM, Lacomis D. The epidemiology of amyotrophic lateral sclerosis. Handb Clin Neurol. 2016;138:225–38.

    CAS  PubMed  Google Scholar 

  92. 92.

    Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377:162–72.

    CAS  PubMed  Google Scholar 

  93. 93.

    Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071.

    PubMed  Google Scholar 

  94. 94.

    Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol. 2011;7:603–15.

    CAS  PubMed  Google Scholar 

  95. 95.

    Rothstein JD. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 2009;65(Suppl 1):S3–9.

    CAS  PubMed  Google Scholar 

  96. 96.

    Smith RA, Miller TM, Yamanaka K, Monia BP, Condon TP, Hung G, et al. Antisense oligonucleotide therapy for neurodegenerative disease. J. Clin. Investig. 2006;116:2290–6.

    CAS  PubMed  Google Scholar 

  97. 97.

    Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 2013;12:435–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    McCampbell A, Cole T, Wegener AJ, Tomassy GS, Setnicka A, Farley BJ, et al. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Investig. 2018;128:3558–67.

    PubMed  Google Scholar 

  99. 99.

    Cudkowicz ME, McKenna-Yasek D, Sapp PE, Chin W, Geller B, Hayden DL, et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol. 1997;41:210–21.

    CAS  PubMed  Google Scholar 

  100. 100.

    Bennett CF, Krainer AR, Cleveland DW. Antisense oligonucleotide therapies for neurodegenerative diseases. Annu Rev Neurosci. 2019;42:385–406.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Berth SH, Lloyd TE. How can an understanding of the C9orf72 gene translate into amyotrophic lateral sclerosis therapies? Expert Rev Neurother. 2019;19:895–7.

    CAS  PubMed  Google Scholar 

  102. 102.

    Jiang J, Ravits J. Pathogenic mechanisms and therapy development for C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia. Neurotherapeutics. 2019;16:1115–32.

    CAS  PubMed  Google Scholar 

  103. 103.

    Cammack AJ, Atassi N, Hyman T, van den Berg LH, Harms M, Baloh RH, et al. Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers. Neurology. 2019;93:e1605–17.

    CAS  PubMed  Google Scholar 

  104. 104.

    Jiang J, Zhu Q, Gendron TF, Saberi S, McAlonis-Downes M, Seelman A, et al. Gain of toxicity from ALS/FTD-Linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs. Neuron. 2016;90:535–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Building a Neuromuscular Franchise: progress in ALS. Biogen. 2019. Accessed May 2020.

  106. 106.

    Klim JR, Vance C, Scotter EL. Antisense oligonucleotide therapies for amyotrophic lateral sclerosis: existing and emerging targets. Int J Biochem Cell Biol. 2019;110:149–53.

    CAS  PubMed  Google Scholar 

  107. 107.

    Ishigaki S, Sobue G. Importance of functional loss of FUS in FTLD/ALS. Front Mol Biosci. 2018;5:44.

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Marangi G, Traynor BJ. Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges. Brain Res. 2015;1607:75–93.

    CAS  PubMed  Google Scholar 

  109. 109.

    Zhou Y, Liu S, Liu G, Öztürk A, Hicks GG. ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation. PLoS Genet. 2013;9:e1003895.

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    Sproviero W, Shatunov A, Stahl D, Shoai M, van Rheenen W, Jones AR, et al. ATXN2 trinucleotide repeat length correlates with risk of ALS. Neurobiol Aging. 2017;51:178.e1–9.

    CAS  Google Scholar 

  111. 111.

    Scoles DR, Meera P, Schneider MD, Paul S, Dansithong W, Figueroa KP, et al. Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature. 2017;544:362–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature. 2017;544:367–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Zhang K, Rothstein JD. Neurodegenerative disease: two-for-one on potential therapies. Nature. 2017;544:302–3.

    CAS  PubMed  Google Scholar 

  114. 114.

    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Ito D, Suzuki N. Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS. Neurology. 2011;77:1636–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pytel KA, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron. 2012;74:1031–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Martin DDO, Kay C, Collins JA, Nguyen YT, Slama RA, Hayden MR. A human huntingtin SNP alters post-translational modification and pathogenic proteolysis of the protein causing Huntington disease. Sci Rep. 2018;8:8096.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Keiser MS, Kordasiewicz HB, McBride JL. Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington’s disease and spinocerebellar ataxia. Hum Mol Genet. 2016;25:R53–64.

    CAS  PubMed  Google Scholar 

  119. 119.

    Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, Wild EJ, Saft C, Barker RA, et al. Targeting Huntingtin expression in patients with Huntington’s disease. N Engl J Med. 2019;380:2307–16.

    CAS  PubMed  Google Scholar 

  120. 120.

    Rodrigues FB, Wild EJ. Huntington’s disease clinical trials corner: February 2018. J Huntingtons Dis. 2018;7:89–98.

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    Rodrigues FB, Quinn L, Wild EJ. Huntington’s disease clinical trials corner: January 2019. J Huntingtons Dis. 2019;8:115–25.

    PubMed  Google Scholar 

  122. 122.

    Evers MM, Pepers BA, van Deutekom JCT, Mulders SAM, den Dunnen JT, Aartsma-Rus A, et al. Targeting several CAG expansion diseases by a single antisense oligonucleotide. PLoS One. 2011;6:e24308.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Datson NA, González-Barriga A, Kourkouta E, Weij R, van de Giessen J, Mulders S, et al. The expanded CAG repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the HD mouse brain. PLoS One. 2017;12:e0171127.

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Kay C, Collins JA, Skotte NH, Southwell AL, Warby SC, Caron NS, et al. Huntingtin haplotypes provide prioritized target panels for allele-specific silencing in huntington disease patients of european ancestry. Mol Ther. 2015;23:1759–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Carroll JB, Warby SC, Southwell AL, Doty CN, Greenlee S, Skotte N, et al. Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the huntington disease gene/allele-specific silencing of mutant Huntingtin. Mol Ther. 2011;19:2178–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Skotte NH, Southwell AL, Østergaard ME, Carroll JB, Warby SC, Doty CN, et al. Allele-specific suppression of mutant Huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients. PLoS One. 2014;9:e107434.

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Southwell AL, Kordasiewicz HB, Langbehn D, Skotte NH, Parsons MP, Villanueva EB, et al. Huntingtin suppression restores cognitive function in a mouse model of Huntington’s disease. Sci. Transl. Med. 2018;10:eaar3959.

    PubMed  Google Scholar 

  128. 128.

    Unpacking Wave’s PRECISION-HD2 huntingtin-lowering trial announcement—HDBuzz: Huntington’s disease research news. Accessed May 2020.

  129. 129.

    Carroll JB, Bates GP, Steffan J, Saft C, Tabrizi SJ. Treating the whole body in Huntington’s disease. Lancet Neurol. 2015;14:1135–42.

    PubMed  Google Scholar 

  130. 130.

    Neil EE, Bisaccia EK. Nusinersen: a novel antisense oligonucleotide for the treatment of spinal muscular atrophy. J Pediatr Pharmacol Ther. 2019;24:194–203.

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    Joshua TC, James DC, Madison CS, Pei-Jung L, Peter JN (2019) Putting the costs and benefits of new gene therapies into perspective. Accessed May 2020.

  132. 132.

    Crudele JM, Chamberlain JS. AAV-based gene therapies for the muscular dystrophies. Hum Mol Genet. 2019;28:R102–7.

    CAS  PubMed  Google Scholar 

  133. 133.

    Le Hir M, Goyenvalle A, Peccate C, Précigout G, Davies KE, Voit T, et al. AAV genome loss from dystrophic mouse muscles during AAV-U7 snRNA-mediated exon-skipping therapy. Mol Ther. 2013;21:1551–8.

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Lee BH, Collins E, Lewis L, Guntrum D, Eichinger K, Voter K, et al. Combination therapy with nusinersen and AVXS-101 in SMA type 1. Neurology. 2019;93:640–1.

    PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Aurélie Goyenvalle.

Ethics declarations

Conflict of interest

AV is an employee of SQY therapeutics, developing tcDNA-ASOs. AG and FB declare no conflict of interest.


Authors are supported by the Institut National de la santé et la recherche médicale (INSERM), the Association Monegasque contre les myopathies (AMM), the Duchenne Parent project France (DPPF) and the Fondation UVSQ. AV is an employee of SQY therapeutics.

Additional information

The original article has been updated: Due to Co-author name update.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bizot, F., Vulin, A. & Goyenvalle, A. Current Status of Antisense Oligonucleotide-Based Therapy in Neuromuscular Disorders. Drugs 80, 1397–1415 (2020).

Download citation