SpringerLink
Log in

Correction of RNA Splicing with Antisense Oligonucleotides as a Therapeutic Strategy for a Neurodegenerative Disease

  • Conference paper
  • First Online:
Chembiomolecular Science

Abstract

Spinal muscular atrophy (SMA) is a severe genetic disease inherited in autosomal recessive fashion. It is the leading genetic cause of infant mortality. SMA is a neuromuscular disease, characterized by progressive degeneration and loss of α-motor neurons in the anterior horn of the spinal cord, which in turn leads to muscle weakness and atrophy, resulting in gradual paralysis. SMA is classified into four types on the basis of severity and time of onset: childhood-onset SMA ranges from type I, which is the most severe, to type III, which is considerably milder, with type II having intermediate severity [1–4]; adult-onset SMA is classified as type IV. There is no effective therapy for SMA.

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

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Munsat TL, Davies KE (1992) International SMA consortium meeting (26–28 June 1992, Bonn, Germany). Neuromuscul Disord 2:423–428

    Article  PubMed  CAS  Google Scholar 

  2. Crawford TO (2003) Spinal muscular atrophies. Butterworth-Heinemann, Philadelphia

    Google Scholar 

  3. Russman BS (2007) Spinal muscular atrophy: clinical classification and disease heterogeneity. J Child Neurol 22:946–951

    Article  PubMed  Google Scholar 

  4. Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO et al (2007) Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol 22:1027–1049

    Article  PubMed  Google Scholar 

  5. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M et al (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155–165

    Article  PubMed  CAS  Google Scholar 

  6. Lorson CL, Hahnen E, Androphy EJ, Wirth B (1999) A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA 96:6307–6311

    Article  PubMed  CAS  Google Scholar 

  7. Cartegni L, Krainer AR (2002) Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat Genet 30:377–384

    Article  PubMed  CAS  Google Scholar 

  8. Kashima T, Manley JL (2003) A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat Genet 34:460–463

    Article  PubMed  CAS  Google Scholar 

  9. Cartegni L, Hastings ML, Calarco JA, de Stanchina E, Krainer AR (2006) Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. Am J Hum Genet 78:63–77

    Article  PubMed  CAS  Google Scholar 

  10. Liu Q, Dreyfuss G (1996) A novel nuclear structure containing the survival of motor neurons protein. EMBO J 15:3555–3565

    PubMed  CAS  Google Scholar 

  11. Meister G, Buhler D, Pillai R, Lottspeich F, Fischer U (2001) A multiprotein complex mediates the ATP-dependent assembly of spliceosomal U snRNPs. Nat Cell Biol 3:945–949

    Article  PubMed  CAS  Google Scholar 

  12. Pellizzoni L, Yong J, Dreyfuss G (2002) Essential role for the SMN complex in the specificity of snRNP assembly. Science 298:1775–1779

    Article  PubMed  CAS  Google Scholar 

  13. Kolb SJ, Battle DJ, Dreyfuss G (2007) Molecular functions of the SMN complex. J Child Neurol 22:990–994

    Article  PubMed  Google Scholar 

  14. Zhang Z, Lotti F, Dittmar K, Younis I, Wan L, Kasim M, Dreyfuss G (2008) SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell 133:585–600

    Article  PubMed  CAS  Google Scholar 

  15. Bäumer D, Lee S, Nicholson G, Davies JL, Parkinson NJ, Murray LM, Gillingwater TH, Ansorge O, Davies KE, Talbot K (2009) Alternative splicing events are a late feature of pathology in a mouse model of spinal muscular atrophy. PLoS Genet 5:e1000773

    Article  PubMed  Google Scholar 

  16. Schrank B, Gotz R, Gunnersen JM, Ure JM, Toyka KV, Smith AG, Sendtner M (1997) Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc Natl Acad Sci USA 94:9920–9925

    Article  PubMed  CAS  Google Scholar 

  17. Hsieh-Li HM, Chang JG, Jong YJ, Wu MH, Wang NM, Tsai CH, Li H (2000) A mouse model for spinal muscular atrophy. Nat Genet 24:66–70

    Article  PubMed  CAS  Google Scholar 

  18. Monani UR, Sendtner M, Coovert DD, Parsons DW, Andreassi C, Le TT, Jablonka S, Schrank B, Rossol W, Prior TW et al (2000) The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn−/− mice and results in a mouse with spinal muscular atrophy. Hum Mol Genet 9:333–339

    Article  PubMed  CAS  Google Scholar 

  19. Lunn MR, Wang CH (2008) Spinal muscular atrophy. Lancet 371:2120–2133

    Article  PubMed  Google Scholar 

  20. Lim SR, Hertel KJ (2001) Modulation of survival motor neuron pre-mRNA splicing by inhibition of alternative 3′ splice site pairing. J Biol Chem 276:45476–45483

    Article  PubMed  CAS  Google Scholar 

  21. Miyajima H, Miyaso H, Okumura M, Kurisu J, Imaizumi K (2002) Identification of a cis-acting element for the regulation of SMN exon 7 splicing. J Biol Chem 277:23271–23277

    Article  PubMed  CAS  Google Scholar 

  22. Cartegni L, Krainer AR (2003) Correction of disease-associated exon skip** by synthetic exon-specific activators. Nat Struct Biol 10:120–125

    Article  PubMed  CAS  Google Scholar 

  23. Skordis LA, Dunckley MG, Yue B, Eperon IC, Muntoni F (2003) Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Proc Natl Acad Sci USA 100:4114–4119

    Article  PubMed  CAS  Google Scholar 

  24. Singh NK, Singh NN, Androphy EJ, Singh RN (2006) 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 26:1333–1346

    Article  PubMed  CAS  Google Scholar 

  25. Coady TH, Shababi M, Tullis GE, Lorson CL (2007) Restoration of SMN function: delivery of a trans-splicing RNA re-directs SMN2 pre-mRNA splicing. Mol Ther 15:1471–1478

    Article  PubMed  CAS  Google Scholar 

  26. Coady TH, Lorson CL (2010) Trans-splicing-mediated improvement in a severe mouse model of spinal muscular atrophy. J Neurosci 30:126–130

    Article  PubMed  CAS  Google Scholar 

  27. Geib T, Hertel KJ (2009) Restoration of full-length SMN promoted by adenoviral vectors expressing RNA antisense oligonucleotides embedded in U7 snRNAs. PLoS One 4:e8204

    Article  PubMed  Google Scholar 

  28. Sendtner M (2010) Therapy development in spinal muscular atrophy. Nat Neurosci 13:795–799

    Article  PubMed  CAS  Google Scholar 

  29. Crooke ST (2001) Basic principles of antisense technology. In: Crooke ST (ed) Antisense drug technology: principles, strategies, and applications. Dekker, New York, pp 1–28

    Chapter  Google Scholar 

  30. Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR (2007) Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol 5:e73

    Article  PubMed  Google Scholar 

  31. Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, Krainer AR (2010) Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev 24:1634–1644

    Article  PubMed  CAS  Google Scholar 

  32. Rigo F, Hua Y, Chun SJ, Prakash TP, Krainer AR, Bennett CF (2012) Synthetic oligonucleotides recruit ILF2/3 to RNA transcripts to modulate splicing. Nat Chem Biol 8:555–561

    Article  PubMed  CAS  Google Scholar 

  33. Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR (2008) Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet 82:834–848

    Article  PubMed  CAS  Google Scholar 

  34. Geary RS, Yu RZ, Watanabe T, Henry SP, Hardee GE, Chappell A, Matson J, Sasmor H, Cummins L, Levin AA (2003) Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2′-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 31:1419–1428

    Article  PubMed  CAS  Google Scholar 

  35. Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP, Stanek LM, Hua Y, Rigo F, Matson J, Hung G, Kaye EM, Shihabuddin LS, Krainer AR, Bennett CF, Cheng SH (2011) Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med 3:72ra18

    Article  PubMed  Google Scholar 

  36. Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett CF, Krainer AR (2010) Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478:123–126

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cold Spring Harbor Laboratory, 1 Bungtown Road, 100, Cold Spring Harbor, NY, 11724, USA

    Yimin Hua, Kentaro Sahashi & Adrian R. Krainer

  2. Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, CA, 92008, USA

    Frank Rigo, Gene Hung & C. Frank Bennett

Authors
  1. Yimin Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kentaro Sahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frank Rigo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gene Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Frank Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adrian R. Krainer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adrian R. Krainer .

Editor information

Editors and Affiliations

  1. Institute of Microbial Chemistry, Kamioosaki 3-14-23, Tokyo, 141-0021, Japan

    Masakatsu Shibasaki

  2. The University of Tokyo, Department of Pharmacology, Graduate School of Medicine, Hongo 7-3-1, Bunkyo-ku, 113-0033, Japan

    Masamitsu Iino

  3. RIKEN Advanced Science Institute, Antibiotics Laboratory, Chemical Biology Core Facility, 2-1, Hirosawa, Wako, 351-0198, Saitama, Japan

    Hiroyuki Osada

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer

About this paper

Cite this paper

Hua, Y., Sahashi, K., Rigo, F., Hung, G., Bennett, C.F., Krainer, A.R. (2012). Correction of RNA Splicing with Antisense Oligonucleotides as a Therapeutic Strategy for a Neurodegenerative Disease. In: Shibasaki, M., Iino, M., Osada, H. (eds) Chembiomolecular Science. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54038-0_30

Download citation

Publish with us

Policies and ethics

Search

Navigation