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

  • Yimin Hua
  • Kentaro Sahashi
  • Frank Rigo
  • Gene Hung
  • C. Frank Bennett
  • Adrian R. Krainer
Conference paper

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.

Keywords

Spinal Muscular Atrophy Survival Motor Neuron Spinal Muscular Atrophy Patient Spinal Muscular Atrophy Type Survival Motor Neuron Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Munsat TL, Davies KE (1992) International SMA consortium meeting (26–28 June 1992, Bonn, Germany). Neuromuscul Disord 2:423–428PubMedCrossRefGoogle Scholar
  2. 2.
    Crawford TO (2003) Spinal muscular atrophies. Butterworth-Heinemann, PhiladelphiaGoogle Scholar
  3. 3.
    Russman BS (2007) Spinal muscular atrophy: clinical classification and disease heterogeneity. J Child Neurol 22:946–951PubMedCrossRefGoogle Scholar
  4. 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 22:1027–1049PubMedCrossRefGoogle Scholar
  5. 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 80:155–165PubMedCrossRefGoogle Scholar
  6. 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 96:6307–6311PubMedCrossRefGoogle Scholar
  7. 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 30:377–384PubMedCrossRefGoogle Scholar
  8. 8.
    Kashima T, Manley JL (2003) A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat Genet 34:460–463PubMedCrossRefGoogle Scholar
  9. 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 78:63–77PubMedCrossRefGoogle Scholar
  10. 10.
    Liu Q, Dreyfuss G (1996) A novel nuclear structure containing the survival of motor neurons protein. EMBO J 15:3555–3565PubMedGoogle Scholar
  11. 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 3:945–949PubMedCrossRefGoogle Scholar
  12. 12.
    Pellizzoni L, Yong J, Dreyfuss G (2002) Essential role for the SMN complex in the specificity of snRNP assembly. Science 298:1775–1779PubMedCrossRefGoogle Scholar
  13. 13.
    Kolb SJ, Battle DJ, Dreyfuss G (2007) Molecular functions of the SMN complex. J Child Neurol 22:990–994PubMedCrossRefGoogle Scholar
  14. 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 133:585–600PubMedCrossRefGoogle Scholar
  15. 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:e1000773PubMedCrossRefGoogle Scholar
  16. 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 94:9920–9925PubMedCrossRefGoogle Scholar
  17. 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 24:66–70PubMedCrossRefGoogle Scholar
  18. 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 9:333–339PubMedCrossRefGoogle Scholar
  19. 19.
    Lunn MR, Wang CH (2008) Spinal muscular atrophy. Lancet 371:2120–2133PubMedCrossRefGoogle Scholar
  20. 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 276:45476–45483PubMedCrossRefGoogle Scholar
  21. 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 277:23271–23277PubMedCrossRefGoogle Scholar
  22. 22.
    Cartegni L, Krainer AR (2003) Correction of disease-associated exon skipping by synthetic exon-specific activators. Nat Struct Biol 10:120–125PubMedCrossRefGoogle Scholar
  23. 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 100:4114–4119PubMedCrossRefGoogle Scholar
  24. 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 26:1333–1346PubMedCrossRefGoogle Scholar
  25. 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 15:1471–1478PubMedCrossRefGoogle Scholar
  26. 26.
    Coady TH, Lorson CL (2010) Trans-splicing-mediated improvement in a severe mouse model of spinal muscular atrophy. J Neurosci 30:126–130PubMedCrossRefGoogle Scholar
  27. 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:e8204PubMedCrossRefGoogle Scholar
  28. 28.
    Sendtner M (2010) Therapy development in spinal muscular atrophy. Nat Neurosci 13:795–799PubMedCrossRefGoogle Scholar
  29. 29.
    Crooke ST (2001) Basic principles of antisense technology. In: Crooke ST (ed) Antisense drug technology: principles, strategies, and applications. Dekker, New York, pp 1–28CrossRefGoogle Scholar
  30. 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:e73PubMedCrossRefGoogle Scholar
  31. 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 24:1634–1644PubMedCrossRefGoogle Scholar
  32. 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 8:555–561PubMedCrossRefGoogle Scholar
  33. 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 82:834–848PubMedCrossRefGoogle Scholar
  34. 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 31:1419–1428PubMedCrossRefGoogle Scholar
  35. 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 3:72ra18PubMedCrossRefGoogle Scholar
  36. 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 478:123–126PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  • Yimin Hua
    • 1
  • Kentaro Sahashi
    • 1
  • Frank Rigo
    • 2
  • Gene Hung
    • 2
  • C. Frank Bennett
    • 2
  • Adrian R. Krainer
    • 1
  1. 1.Cold Spring Harbor LaboratoryCold Spring HarborUSA
  2. 2.Isis PharmaceuticalsCarlsbadUSA

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