Skip to main content

Advertisement

SpringerLink
Log in

Antisense Oligonucleotide Therapeutics for Neurodegenerative Disorders

  • Neurology of Aging (K Marder, Section Editor)
  • Published:
Current Geriatrics Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Expanding therapeutic targets from proteins to RNAs opens up new possibilities for neurodegenerative disorders therapeutics development. Recently, a disease-modifying antisense oligonucleotide (ASO) agent was approved for spinal muscular atrophy, suggesting ASOs will fulfill their early promise and become a significant new therapeutic category for neurodegenerative disorders.

Recent Findings

ASOs are in human subjects testing for Huntington disease, monogenic forms of amyotrophic lateral sclerosis, Alzheimer disease, myotonic dystrophy, Leber congenital amaurosis, Usher syndrome, and retinitis pigmentosum, with many more in preclinical development. Current ASO strategies encompass RNA processing modulation, and RNA target breakdown. Broad ASO mechanism categories are protein restoring versus protein lowering. Individual ASO mechanisms of action range from mutation-specific to impacting many proteins.

Summary

Current ASOs show great promise in neurodegenerative disorders. Specific ASO designs and mechanisms may be more tenable in this disease area. Preclinical development is already leveraging early knowledge from these initial clinical trials to develop novel ASO cocktails, new ASO chemical modifications, and new ASO RNA and protein targets.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Crooke ST, Lemonidis KM, Neilson L, Griffey R, Lesnik EA, Monia BP. Kinetic characteristics of Escherichia coli RNase H1: cleavage of various antisense oligonucleotide-RNA duplexes. Biochem J. 1995;312(Pt 2):599–608. https://doi.org/10.1042/bj3120599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gao WY, Han FS, Storm C, Egan W, Cheng YC. Phosphorothioate oligonucleotides are inhibitors of human DNA polymerases and RNase H: implications for antisense technology. Mol Pharmacol. 1992;41(2):223–9.

    CAS  PubMed  Google Scholar 

  3. • Bennett CF. Therapeutic antisense oligonucleotides are coming of age. Annu Rev Med. 2019;70:307–21. https://doi.org/10.1146/annurev-med-041217-010829Overview of ASO therapeutic strategies and pharmacology focused on clinically available agents.

    Article  CAS  PubMed  Google Scholar 

  4. Scoles DR, Pulst SM. Oligonucleotide therapeutics in neurodegenerative diseases. RNA Biol. 2018;15(6):707–14. https://doi.org/10.1080/15476286.2018.1454812.

    Article  PubMed  PubMed Central  Google Scholar 

  5. • Egli M, Manoharan M. Re-engineering RNA molecules into therapeutic agents. Acc Chem Res. 2019;52(4):1036–47. https://doi.org/10.1021/acs.accounts.8b00650Detailed look at chemical modifications and their impact on nucleic acids as therapeutics.

    Article  CAS  PubMed  Google Scholar 

  6. Crooke ST, Wang S, Vickers TA, Shen W, Liang XH. Cellular uptake and trafficking of antisense oligonucleotides. Nat Biotechnol. 2017;35(3):230–7. https://doi.org/10.1038/nbt.3779.

    Article  CAS  PubMed  Google Scholar 

  7. Geary RS, Norris D, Yu R, Bennett CF. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev. 2015;87:46–51. https://doi.org/10.1016/j.addr.2015.01.008.

    Article  CAS  PubMed  Google Scholar 

  8. Rigo F, Chun SJ, Norris DA, Hung G, Lee S, Matson J, et al. Pharmacology of a central nervous system delivered 2'-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. J Pharmacol Exp Ther. 2014;350(1):46–55. https://doi.org/10.1124/jpet.113.212407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. •• Bennett CF, Baker BF, Pham N, Swayze E, Geary RS. Pharmacology of Antisense Drugs. Annu Rev Pharmacol Toxicol. 2017;57:81–105. https://doi.org/10.1146/annurev-pharmtox-010716-104846Detailed review of ASO chemical modifications, pharmacokinetics, toxicology.

    Article  CAS  PubMed  Google Scholar 

  10. Monia BP, Lesnik EA, Gonzalez C, Lima WF, McGee D, Guinosso CJ, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem. 1993;268(19):14514–22.

    Article  CAS  Google Scholar 

  11. Sharp PA. The centrality of RNA. Cell. 2009;136(4):577–80. https://doi.org/10.1016/j.cell.2009.02.007.

    Article  CAS  PubMed  Google Scholar 

  12. Goff LA, Rinn JL. Linking RNA biology to lncRNAs. Genome Res. 2015;25(10):1456–65. https://doi.org/10.1101/gr.191122.115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bartel DP. Metazoan MicroRNAs. Cell. 2018;173(1):20–51. https://doi.org/10.1016/j.cell.2018.03.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Woo CJ, Maier VK, Davey R, Brennan J, Li G, Brothers J 2nd, et al. Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy. Proc Natl Acad Sci U S A. 2017;114(8):E1509–E18. https://doi.org/10.1073/pnas.1616521114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu J, Sun X. Complement system and age-related macular degeneration: drugs and challenges. Drug Des Devel Ther. 2019;13:2413–25. https://doi.org/10.2147/DDDT.S206355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–65. https://doi.org/10.1016/0092-8674(95)90460-3.

    Article  CAS  PubMed  Google Scholar 

  17. 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(10063):3017–26. https://doi.org/10.1016/S0140-6736(16)31408-8.

    Article  CAS  PubMed  Google Scholar 

  18. • Vazquez-Dominguez I, Garanto A, Collin RWJ. Molecular therapies for inherited retinal diseases-current standing, opportunities and challenges. Genes (Basel). 2019;10(9). https://doi.org/10.3390/genes10090654Overview of a key growing area in molecular therapeutics for neurodegenerative disorders.

  19. Rowe-Rendleman CL, Durazo SA, Kompella UB, Rittenhouse KD, Di Polo A, Weiner AL, et al. Drug and gene delivery to the back of the eye: from bench to bedside. Invest Ophthalmol Vis Sci. 2014;55(4):2714–30. https://doi.org/10.1167/iovs.13-13707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vitravene Study G. Safety of intravitreous fomivirsen for treatment of cytomegalovirus retinitis in patients with AIDS. Am J Ophthalmol. 2002;133(4):484–98. https://doi.org/10.1016/s0002-9394(02)01332-6.

    Article  Google Scholar 

  21. Vitravene Study G. A randomized controlled clinical trial of intravitreous fomivirsen for treatment of newly diagnosed peripheral cytomegalovirus retinitis in patients with AIDS. Am J Ophthalmol. 2002;133(4):467–74. https://doi.org/10.1016/s0002-9394(02)01327-2.

    Article  Google Scholar 

  22. Khan M, Fadaie Z, Cornelis SS, Cremers FPM, Roosing S. Identification and analysis of genes associated with inherited retinal diseases. Methods Mol Biol. 1834;2019:3–27. https://doi.org/10.1007/978-1-4939-8669-9_1.

    Article  CAS  Google Scholar 

  23. Hammond SM, Wood MJ. Genetic therapies for RNA mis-splicing diseases. Trends Genet. 2011;27(5):196–205. https://doi.org/10.1016/j.tig.2011.02.004.

    Article  CAS  PubMed  Google Scholar 

  24. Bacchi N, Casarosa S, Denti MA. Splicing-correcting therapeutic approaches for retinal dystrophies: where endogenous gene regulation and specificity matter. Invest Ophthalmol Vis Sci. 2014;55(5):3285–94. https://doi.org/10.1167/iovs.14-14544.

    Article  CAS  PubMed  Google Scholar 

  25. den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, et al. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet. 2006;79(3):556–61. https://doi.org/10.1086/507318.

    Article  Google Scholar 

  26. Dulla K, Aguila M, Lane A, Jovanovic K, Parfitt DA, Schulkens I, et al. Splice-modulating oligonucleotide QR-110 restores CEP290 mRNA and function in human c.2991+1655A>G LCA10 models. Mol Ther Nucleic Acids. 2018;12:730–40. https://doi.org/10.1016/j.omtn.2018.07.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. •• Cideciyan AV, Jacobson SG, Drack AV, Ho AC, Charng J, Garafalo AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med. 2019;25(2):225–8. https://doi.org/10.1038/s41591-018-0295-0Although this is a small open label study, it is one of very few peer-reviewed publications of clinical trial data in this field.

    Article  CAS  PubMed  Google Scholar 

  28. Mathur P, Yang J. Usher syndrome: hearing loss, retinal degeneration and associated abnormalities. Biochim Biophys Acta. 2015;1852(3):406–20. https://doi.org/10.1016/j.bbadis.2014.11.020.

    Article  CAS  PubMed  Google Scholar 

  29. • Hastings ML, Jones TA. Antisense Oligonucleotides for the Treatment of Inner Ear Dysfunction. Neurotherapeutics. 2019;16(2):348–59. https://doi.org/10.1007/s13311-019-00729-0Overview of pros and cons of ASO therapeutics in a distinct area of neurological disease.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yan D, Liu XZ. Genetics and pathological mechanisms of usher syndrome. J Hum Genet. 2010;55(6):327–35. https://doi.org/10.1038/jhg.2010.29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yan D, Ouyang X, Patterson DM, Du LL, Jacobson SG, Liu XZ. Mutation analysis in the long isoform of USH2A in American patients with usher syndrome type II. J Hum Genet. 2009;54(12):732–8. https://doi.org/10.1038/jhg.2009.107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. •• Li D, Mastaglia FL, Fletcher S, Wilton SD. Precision medicine through antisense oligonucleotide-mediated exon skipping. Trends Pharmacol Sci. 2018;39(11):982–94. https://doi.org/10.1016/j.tips.2018.09.001.detailsWork on a specific ASO strategy relevant to neurodegenerative and other neurological disorders.

    Article  PubMed  Google Scholar 

  33. Al-Chalabi A, Durr A, Wood NW, Parkinson MH, Camuzat A, Hulot JS, et al. Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy. PLoS One. 2009;4(9):e7114. https://doi.org/10.1371/journal.pone.0007114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362(6415):59–62.

    Article  CAS  Google Scholar 

  35. • Ly CV, Miller TM. Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis. Curr Opin Neurol. 2018;31(5):648–54. https://doi.org/10.1097/WCO.0000000000000594Covers clinical and pre-clinical work relevant to ALS and other neurodegenerative disorders.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Marangi G, Traynor BJ. Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges. Brain Res. 1607;2015:75–93. https://doi.org/10.1016/j.brainres.2014.10.009.

    Article  CAS  Google Scholar 

  37. 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(5):435–42. https://doi.org/10.1016/S1474-4422(13)70061-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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 Invest. 2018;128(8):3558–67. https://doi.org/10.1172/JCI99081.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Miller TM, Cudkowicz ME, Shaw PJ, Graham D, Fradette S, Houshyar H, et al. Safety, PK, PD, and exploratory efficacy in a single and multiple-dose study of a SOD1 antisense oligonucleotide (BIIB067) administered to participants with ALS. Neurology. 2019;92(15 Supplement):Emerging Science Abstracts. https://doi.org/10.1212/WNL.0000000000007887.

    Article  Google Scholar 

  40. Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurol. 2013;12(6):609–22. https://doi.org/10.1016/S1474-4422(13)70090-5.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang CC, Zhu JX, Wan Y, Tan L, Wang HF, Yu JT, et al. Meta-analysis of the association between variants in MAPT and neurodegenerative diseases. Oncotarget. 2017;8(27):44994–5007. https://doi.org/10.18632/oncotarget.16690.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Schoch KM, DeVos SL, Miller RL, Chun SJ, Norrbom M, Wozniak DF, et al. Increased 4R-tau induces pathological changes in a human-tau mouse model. Neuron. 2016;90(5):941–7. https://doi.org/10.1016/j.neuron.2016.04.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017;9(374). https://doi.org/10.1126/scitranslmed.aag0481.

  44. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59. https://doi.org/10.1007/BF00308809.

    Article  CAS  PubMed  Google Scholar 

  45. Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011;70(11):960–9. https://doi.org/10.1097/NEN.0b013e318232a379.

    Article  CAS  PubMed  Google Scholar 

  46. •• 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(24):2307–16. https://doi.org/10.1056/NEJMoa1900907Peer reviewed report of initial clinical trial data for an ASO in a CNS-based neurodegenerative disease.

    Article  CAS  PubMed  Google Scholar 

  47. Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, et al. Huntington disease. Nat Rev Dis Primers. 2015;1:15005. https://doi.org/10.1038/nrdp.2015.5.

    Article  PubMed  Google Scholar 

  48. Saudou F, Humbert S. The biology of Huntingtin. Neuron. 2016;89(5):910–26. https://doi.org/10.1016/j.neuron.2016.02.003.

    Article  CAS  PubMed  Google Scholar 

  49. • Wiatr K, Szlachcic WJ, Trzeciak M, Figlerowicz M, Figiel M. Huntington Disease as a neurodevelopmental disorder and early Signs of the Disease in Stem Cells. Mol Neurobiol. 2018;55(4):3351–71. https://doi.org/10.1007/s12035-017-0477-7Important concepts to consider in non-allele specific protein lowering therapeutic strategies, even for apparently straightforward autosomal dominant mutations.

    Article  CAS  PubMed  Google Scholar 

  50. Lee JM, Ramos EM, Lee JH, Gillis T, Mysore JS, Hayden MR, et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology. 2012;78(10):690–5. https://doi.org/10.1212/WNL.0b013e318249f683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gusella JF, MacDonald ME, Lee JM. Genetic modifiers of Huntington’s disease. Mov Disord. 2014;29(11):1359–65. https://doi.org/10.1002/mds.26001.

    Article  CAS  PubMed  Google Scholar 

  52. Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, et al. Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain. 2003;126(Pt 4):946–55. https://doi.org/10.1093/brain/awg077.

    Article  PubMed  Google Scholar 

  53. Ganesh A, Galetta S. Editors’ note: clinical manifestations of homozygote allele carriers in Huntington disease. Neurology. 2020;94(16):722. https://doi.org/10.1212/WNL.0000000000009305.

    Article  Google Scholar 

  54. Cubo E, Martinez-Horta SI, Santalo FS, Descalls AM, Calvo S, Gil-Polo C, et al. Clinical manifestations of homozygote allele carriers in Huntington disease. Neurology. 2019;92(18):e2101–e8. https://doi.org/10.1212/WNL.0000000000007147.

    Article  CAS  PubMed  Google Scholar 

  55. Squitieri F, Andrew SE, Goldberg YP, Kremer B, Spence N, Zeisler J, et al. DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence. Hum Mol Genet. 1994;3(12):2103–14.

    Article  CAS  Google Scholar 

  56. Warby SC, Visscher H, Collins JA, Doty CN, Carter C, Butland SL, et al. HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia. Eur J Hum Genet. 2011;19(5):561–6. https://doi.org/10.1038/ejhg.2010.229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kay C, Hayden MR, Leavitt BR. Epidemiology of Huntington disease. Handb Clin Neurol. 2017;144:31–46. https://doi.org/10.1016/B978-0-12-801893-4.00003-1.

    Article  PubMed  Google Scholar 

  58. Pfister EL, Kennington L, Straubhaar J, Wagh S, Liu W, DiFiglia M, et al. Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients. Curr Biol. 2009;19(9):774–8. https://doi.org/10.1016/j.cub.2009.03.030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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(11):1759–71. https://doi.org/10.1038/mt.2015.128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Castilhos RM, Augustin MC, Santos JA, Perandones C, Saraiva-Pereira ML, Jardim LB, et al. Genetic aspects of Huntington’s disease in Latin America. A systematic review. Clin Genet. 2016;89(3):295–303. https://doi.org/10.1111/cge.12641.

    Article  CAS  PubMed  Google Scholar 

  61. Baine FK, Kay C, Ketelaar ME, Collins JA, Semaka A, Doty CN, et al. Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes. Eur J Hum Genet. 2013;21(10):1120–7. https://doi.org/10.1038/ejhg.2013.2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. •• Kay C, Collins JA, Caron NS, Agostinho LA, Findlay-Black H, Casal L, et al. A comprehensive haplotype-targeting strategy for Aallele-specific HTT suppression in Huntington disease. Am J Hum Genet. 2019;105(6):1112–25. https://doi.org/10.1016/j.ajhg.2019.10.011. Key considerations in any haplotype-dependent ASO therapeutic strategy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Pulkes T, Papsing C, Wattanapokayakit S, Mahasirimongkol S. CAG-expansion haplotype analysis in a population with a low prevalence of Huntington’s disease. J Clin Neurol. 2014;10(1):32–6. https://doi.org/10.3988/jcn.2014.10.1.32.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurol. 2017;16(10):837–47. https://doi.org/10.1016/S1474-4422(17)30280-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Iwamoto N, Butler DCD, Svrzikapa N, Mohapatra S, Zlatev I, Sah DWY, et al. Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nat Biotechnol. 2017;35(9):845–51. https://doi.org/10.1038/nbt.3948.

    Article  CAS  PubMed  Google Scholar 

  66. Dryja TP, McGee TL, Reichel E, Hahn LB, Cowley GS, Yandell DW, et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature. 1990;343(6256):364–6. https://doi.org/10.1038/343364a0.

    Article  CAS  PubMed  Google Scholar 

  67. Sullivan LS, Bowne SJ, Birch DG, Hughbanks-Wheaton D, Heckenlively JR, Lewis RA, et al. Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families. Invest Ophthalmol Vis Sci. 2006;47(7):3052–64. https://doi.org/10.1167/iovs.05-1443.

    Article  PubMed  Google Scholar 

  68. Talib M, Boon CJF. Retinal dystrophies and the road to treatment: clinical requirements and considerations. Asia Pac J Ophthalmol (Phila). 2020;9(3):159–79. https://doi.org/10.1097/APO.0000000000000290.

    Article  Google Scholar 

  69. Murray SF, Jazayeri A, Matthes MT, Yasumura D, Yang H, Peralta R, et al. Allele-specific inhibition of rhodopsin with an antisense oligonucleotide slows photoreceptor cell degeneration. Invest Ophthalmol Vis Sci. 2015;56(11):6362–75. https://doi.org/10.1167/iovs.15-16400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. •• Chen KW, Chen JA. Functional roles of long non-coding RNAs in motor neuron development and disease. J Biomed Sci. 2020;27(1):38. https://doi.org/10.1186/s12929-020-00628-zKey concepts relevant to ASO therapeutics development across lncRNA-based neurological disorders.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Todd PK, Paulson HL. RNA-mediated neurodegeneration in repeat expansion disorders. Ann Neurol. 2010;67(3):291–300. https://doi.org/10.1002/ana.21948.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Thornton CA. Myotonic dystrophy. Neurol Clin. 2014;32(3):705–19, viii. https://doi.org/10.1016/j.ncl.2014.04.011.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Meola G, Cardani R. Myotonic dystrophies: an update on clinical aspects, genetic, pathology, and molecular pathomechanisms. Biochim Biophys Acta. 2015;1852(4):594–606. https://doi.org/10.1016/j.bbadis.2014.05.019.

    Article  CAS  PubMed  Google Scholar 

  74. •• Thornton CA, Wang E, Carrell EM. Myotonic dystrophy: approach to therapy. Curr Opin Genet Dev. 2017;44:135–40. https://doi.org/10.1016/j.gde.2017.03.007Key concepts relevant to ASO therapeutics design across lncRNA-based neurological disorders, particularly multisystem disorders and disorders where lncRNA pathology has wide-ranging primary and secondary impacts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Musova Z, Mazanec R, Krepelova A, Ehler E, Vales J, Jaklova R, et al. Highly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene. Am J Med Genet A. 2009;149A(7):1365–74. https://doi.org/10.1002/ajmg.a.32987.

    Article  CAS  PubMed  Google Scholar 

  76. Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, 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;69(2):385. https://doi.org/10.1016/0092-8674(92)90418-c.

    Article  CAS  PubMed  Google Scholar 

  77. 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(7409):111–5. https://doi.org/10.1038/nature11362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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(2):329–40. https://doi.org/10.1124/jpet.115.226969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Mignon L. https://www.myotonic.org/sites/default/files/pages/files/Laurence-Mignon_IONIS-Update_2018-Conference.pdf. Myotonic Dystrophy Foundation meeting 2018.

  80. Yadava RS, Yu Q, Mandal M, Rigo F, Bennett CF, Mahadevan MS. Systemic therapy in a RNA toxicity mouse model with an antisense oligonucleotide therapy targeting a non-CUG sequence within the DMPK 3'UTR RNA. Hum Mol Genet. 2020;29:1440–53. https://doi.org/10.1093/hmg/ddaa060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 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 Invest. 2019;129(11):4739–44. https://doi.org/10.1172/JCI128205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Christou M, Wengel J, Sokratous K, Kyriacou K, Nikolaou G, Phylactou LA, et al. Systemic evaluation of chimeric LNA/2'-O-methyl steric blockers for myotonic dystrophy type 1 therapy. Nucleic Acid Ther. 2020;30(2):80–93. https://doi.org/10.1089/nat.2019.0811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Stepniak-Konieczna E, Konieczny P, Cywoniuk P, Dluzewska J, Sobczak K. AON-induced splice-switching and DMPK pre-mRNA degradation as potential therapeutic approaches for myotonic dystrophy type 1. Nucleic Acids Res. 2020;48(5):2531–43. https://doi.org/10.1093/nar/gkaa007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jamal GA, Weir AI, Hansen S, Ballantyne JP. Myotonic dystrophy. A reassessment by conventional and more recently introduced neurophysiological techniques. Brain. 1986;109(Pt 6):1279–96. https://doi.org/10.1093/brain/109.6.1279.

    Article  PubMed  Google Scholar 

  85. Labayru G, Diez I, Sepulcre J, Fernandez E, Zulaica M, Cortes JM, et al. Regional brain atrophy in gray and white matter is associated with cognitive impairment in Myotonic dystrophy type 1. Neuroimage Clin. 2019;24:102078. https://doi.org/10.1016/j.nicl.2019.102078.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Abramzon YA, Fratta P, Traynor BJ, Chia R. The overlapping genetics of amyotrophic lateral sclerosis and frontotemporal dementia. Front Neurosci. 2020;14:42. https://doi.org/10.3389/fnins.2020.00042.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Ling SC, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416–38. https://doi.org/10.1016/j.neuron.2013.07.033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245–56. https://doi.org/10.1016/j.neuron.2011.09.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72(2):257–68. https://doi.org/10.1016/j.neuron.2011.09.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11(4):323–30. https://doi.org/10.1016/S1474-4422(12)70043-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rademakers R. C9orf72 repeat expansions in patients with ALS and FTD. Lancet Neurol. 2012;11(4):297–8. https://doi.org/10.1016/S1474-4422(12)70046-7.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Haeusler AR, Donnelly CJ, Rothstein JD. The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease. Nat Rev Neurosci. 2016;17(6):383–95. https://doi.org/10.1038/nrn.2016.38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Cappella M, Ciotti C, Cohen-Tannoudji M, Biferi MG. Gene therapy for ALS-a perspective. Int J Mol Sci. 2019;20(18). https://doi.org/10.3390/ijms20184388.

  94. Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li HR, et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013;110(47):E4530–9. https://doi.org/10.1073/pnas.1318835110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 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(3):535–50. https://doi.org/10.1016/j.neuron.2016.04.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Frazier KS. Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist’s perspective. Toxicol Pathol. 2015;43(1):78–89. https://doi.org/10.1177/0192623314551840.

    Article  CAS  PubMed  Google Scholar 

  97. Aupy P, Echevarria L, Relizani K, Zarrouki F, Haeberli A, Komisarski M, et al. Identifying and avoiding tcDNA-ASO sequence-specific toxicity for the development of DMD exon 51 skipping therapy. Mol Ther Nucleic Acids. 2020;19:371–83. https://doi.org/10.1016/j.omtn.2019.11.020.

    Article  CAS  PubMed  Google Scholar 

  98. 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(3):121–9. https://doi.org/10.1089/nat.2016.0650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Schoch KM, Miller TM. Antisense oligonucleotides: translation from mouse models to human neurodegenerative diseases. Neuron. 2017;94(6):1056–70. https://doi.org/10.1016/j.neuron.2017.04.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wild EJ, Tabrizi SJ. Targets for future clinical trials in Huntington’s disease: what’s in the pipeline? Mov Disord. 2014;29(11):1434–45. https://doi.org/10.1002/mds.26007.

    Article  CAS  PubMed  Google Scholar 

  101. Ammala C, Drury WJ 3rd, Knerr L, Ahlstedt I, Stillemark-Billton P, Wennberg-Huldt C, et al. Targeted delivery of antisense oligonucleotides to pancreatic beta-cells. Sci Adv. 2018;4(10):eaat3386. https://doi.org/10.1126/sciadv.aat3386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Huang Y. Preclinical and clinical advances of GalNAc-decorated nucleic acid therapeutics. Mol Ther Nucleic Acids. 2017;6:116–32. https://doi.org/10.1016/j.omtn.2016.12.003.

    Article  CAS  PubMed  Google Scholar 

  103. Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ, Baker BF, et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet. 2015;386(10002):1472–83. https://doi.org/10.1016/S0140-6736(15)61252-1.

    Article  CAS  PubMed  Google Scholar 

  104. Sathasivam K, Neueder A, Gipson TA, Landles C, Benjamin AC, Bondulich MK, et al. Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc Natl Acad Sci U S A. 2013;110(6):2366–70. https://doi.org/10.1073/pnas.1221891110.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Michel L, Huguet-Lachon A, Gourdon G. Sense and antisense DMPK RNA foci accumulate in DM1 tissues during development. PLoS One. 2015;10(9):e0137620. https://doi.org/10.1371/journal.pone.0137620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. De Vivo DC, Bertini E, Swoboda KJ, Hwu WL, Crawford TO, Finkel RS, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the phase 2 NURTURE study. Neuromuscul Disord. 2019;29(11):842–56. https://doi.org/10.1016/j.nmd.2019.09.007.

    Article  PubMed  PubMed Central  Google Scholar 

  107. • Testa CM, Jankovic J. Huntington disease: a quarter century of progress since the gene discovery. J Neurol Sci. 2019;396:52–68. https://doi.org/10.1016/j.jns.2018.09.022Includes framework for understanding challenges for early therapeutic intervention concepts, particularly for neurodegenerative disorders with a wide phenotype range.

    Article  CAS  PubMed  Google Scholar 

  108. • Aartsma-Rus A, Straub V, Hemmings R, Haas M, Schlosser-Weber G, Stoyanova-Beninska V, et al. Development of exon skipping therapies for Duchenne muscular dystrophy: a critical review and a perspective on the outstanding issues. Nucleic Acid Ther. 2017;27(5):251–9. https://doi.org/10.1089/nat.2017.0682Covers key ASO therapeutics challenges around treating the full patient population in a multi-etiology disorder, such as use of ASO cocktails within one therapeutic.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Rodrigues FB, Quinn L, Wild EJ. Huntington’s disease clinical trials corner: January 2019. J Huntingtons Dis. 2019;8(1):115–25. https://doi.org/10.3233/JHD-190001.

    Article  PubMed  Google Scholar 

  110. Bali T, Self W, Liu J, Siddique T, Wang LH, Bird TD, et al. Defining SOD1 ALS natural history to guide therapeutic clinical trial design. J Neurol Neurosurg Psychiatry. 2017;88(2):99–105. https://doi.org/10.1136/jnnp-2016-313521.

    Article  PubMed  Google Scholar 

  111. Hubers A, Just W, Rosenbohm A, Muller K, Marroquin N, Goebel I, et al. De novo FUS mutations are the most frequent genetic cause in early-onset German ALS patients. Neurobiol Aging. 2015;36(11):3117 e1-e6. https://doi.org/10.1016/j.neurobiolaging.2015.08.005.

    Article  CAS  PubMed  Google Scholar 

  112. Conte A, Lattante S, Zollino M, Marangi G, Luigetti M, Del Grande A, et al. P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis. Neuromuscul Disord. 2012;22(1):73–5. https://doi.org/10.1016/j.nmd.2011.08.003.

    Article  PubMed  Google Scholar 

  113. Deusterward R. https://patientworthy.com/2019/06/10/the-fda-congress-a-young-woman-dying-of-als-her-physician-and-her-parents-are-all-struggling-over-access-to-an-untested-therapy/. 2019.

  114. https://siouxcityjournal.com/news/local/obituaries/jaci-j-hermstad/article_c5bcc6a6-c14a-5dbb-a17a-7ce4c81b5b4c.html. 2020.

  115. Figueiredo M. https://alsnewstoday.com/2020/03/16/jacifusen-collaboration-funds-experimental-therapy-for-patients-with-rare-fus-als/. ALS News Today. 2020.

  116. Thakur N. https://www.als.org/stories-news/deeper-look-als-association-efforts-speed-approval-gene-therapies. 2020.

  117. • Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16(3):203–22. https://doi.org/10.1038/nrd.2016.246A look at a potential new ASO therapeutic class.

    Article  CAS  PubMed  Google Scholar 

  118. d'Ydewalle C, Ramos DM, Pyles NJ, Ng SY, Gorz M, Pilato CM, et al. The antisense transcript SMN-AS1 regulates SMN expression and is a novel therapeutic target for spinal muscular atrophy. Neuron. 2017;93(1):66–79. https://doi.org/10.1016/j.neuron.2016.11.033.

    Article  CAS  PubMed  Google Scholar 

  119. Zhang K, Daigle JG, Cunningham KM, Coyne AN, Ruan K, Grima JC, et al. Stress granule assembly disrupts nucleocytoplasmic transport. Cell. 2018;173(4):958–71 e17. https://doi.org/10.1016/j.cell.2018.03.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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(7650):367–71. https://doi.org/10.1038/nature22038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Carroll JB, Bates GP, Steffan J, Saft C, Tabrizi SJ. Treating the whole body in Huntington’s disease. Lancet Neurol. 2015;14(11):1135–42. https://doi.org/10.1016/S1474-4422(15)00177-5.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Parkinson’s and Movement Disorders Center, VCU Department of Neurology, Virginia Commonwealth University, 1101 East Marshall Street, 6th Floor Sanger Hall, Room 6-013, Richmond, VA, 23298, USA

    Claudia M. Testa

Authors
  1. Claudia M. Testa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claudia M. Testa.

Ethics declarations

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Neurology of Aging

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Testa, C.M. Antisense Oligonucleotide Therapeutics for Neurodegenerative Disorders. Curr Geri Rep 11, 19–32 (2022). https://doi.org/10.1007/s13670-020-00341-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13670-020-00341-7

Keywords

Search

Navigation