Skip to main content
SpringerLink
Log in

Therapeutic Development in Myotonic Dystrophy

  • Chapter
  • First Online:
Myotonic Dystrophy

  • 609 Accesses

Abstract

Myotonic dystrophy (DM) is the most common form of muscular dystrophy in adults, caused by unstable genomic expansions of CTG or CCTG repeats. The mutant RNA transcripts containing expanded repeats cause a toxic gain-of-function by perturbing splicing factors in the nucleus, resulting in misregulation of alternative pre-mRNA splicing. Recent advances in basic and translational research and pharmacological approaches provide clues for therapeutic intervention in DM. Here, we review the therapeutic approaches for targeting the toxic RNA with antisense oligonucleotides and small molecules.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Nakamori M, Takahashi MP. Myotonic dystrophy. In: Takeda S, Miyagoe-Suzuki Y, Yoshimura M, editors. Translational research in muscular dystrophy. Tokyo: Springer; 2016. p. 39–61.

    Chapter  Google Scholar 

  2. Nakamori M, Thornton C. Epigenetic changes and non-coding expanded repeats. Neurobiol Dis. 2010;39(1):21–7. https://doi.org/10.1016/j.nbd.2010.02.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, Moxley RT, et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell. 2002;10(1):35–44.

    Article  CAS  Google Scholar 

  4. Savkur RS, Philips AV, Cooper TA. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet. 2001;29(1):40–7.

    Article  CAS  Google Scholar 

  5. Kimura T, Nakamori M, Lueck JD, Pouliquin P, Aoike F, Fujimura H, et al. Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1. Hum Mol Genet. 2005;14(15):2189–200.

    Article  CAS  Google Scholar 

  6. Nakamori M, Kimura T, Fujimura H, Takahashi MP, Sakoda S. Altered mRNA splicing of dystrophin in type 1 myotonic dystrophy. Muscle Nerve. 2007;36(2):251–7. https://doi.org/10.1002/mus.20809.

    Article  CAS  PubMed  Google Scholar 

  7. Nakamori M, Kimura T, Kubota T, Matsumura T, Sumi H, Fujimura H, et al. Aberrantly spliced alpha-dystrobrevin alters alpha-syntrophin binding in myotonic dystrophy type 1. Neurology. 2008;70(9):677–85. https://doi.org/10.1212/01.wnl.0000302174.08951.cf.

    Article  CAS  PubMed  Google Scholar 

  8. Tang ZZ, Yarotskyy V, Wei L, Sobczak K, Nakamori M, Eichinger K, et al. Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of CaV1.1 calcium channel. Hum Mol Genet. 2012;21(6):1312–24. https://doi.org/10.1093/hmg/ddr568.

    Article  CAS  PubMed  Google Scholar 

  9. Nakamori M, Sobczak K, Puwanant A, Welle S, Eichinger K, Pandya S, et al. Splicing biomarkers of disease severity in myotonic dystrophy. Ann Neurol. 2013;74(6):862–72. https://doi.org/10.1002/ana.23992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Freyermuth F, Rau F, Kokunai Y, Linke T, Sellier C, Nakamori M, et al. Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nat Commun. 2016;7:11067. https://doi.org/10.1038/ncomms11067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Southwell AL, Skotte NH, Bennett CF, Hayden MR. Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases. Trends Mol Med. 2012;18(11):634–43. https://doi.org/10.1016/j.molmed.2012.09.001.

    Article  CAS  PubMed  Google Scholar 

  12. Koo T, Wood MJ. Clinical trials using antisense oligonucleotides in duchenne muscular dystrophy. Hum Gene Ther. 2013;24(5):479–88. https://doi.org/10.1089/hum.2012.234.

    Article  CAS  PubMed  Google Scholar 

  13. 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 Invest. 2007;117(12):3952–7. https://doi.org/10.1172/JCI33355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kanadia RN, Johnstone KA, Mankodi A, Lungu C, Thornton CA, Esson D, et al. A muscleblind knockout model for myotonic dystrophy. Science. 2003;302(5652):1978–80.

    Article  CAS  Google Scholar 

  15. Kanadia RN, Shin J, Yuan Y, Beattie SG, Wheeler TM, Thornton CA, et al. Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proc Natl Acad Sci U S A. 2006;103(31):11748–53.

    Article  CAS  Google Scholar 

  16. Roberts R, Timchenko NA, Miller JW, Reddy S, Caskey CT, Swanson MS, et al. Altered phosphorylation and intracellular distribution of a (CUG)n triplet repeat RNA-binding protein in patients with myotonic dystrophy and in myotonin protein kinase knockout mice. Proc Natl Acad Sci U S A. 1997;94(24):13221–6.

    Article  CAS  Google Scholar 

  17. Ho TH, Bundman D, Armstrong DL, Cooper TA. Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy. Hum Mol Genet. 2005;14(11):1539–47.

    Article  CAS  Google Scholar 

  18. Ward AJ, Rimer M, Killian JM, Dowling JJ, Cooper TA. CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1. Hum Mol Genet. 2010;19(18):3614–22. https://doi.org/10.1093/hmg/ddq277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Koshelev M, Sarma S, Price RE, Wehrens XH, Cooper TA. Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1. Hum Mol Genet. 2010;19(6):1066–75. https://doi.org/10.1093/hmg/ddp570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kuyumcu-Martinez NM, Wang GS, Cooper TA. Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol Cell. 2007;28(1):68–78. https://doi.org/10.1016/j.molcel.2007.07.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang GS, Kuyumcu-Martinez MN, Sarma S, Mathur N, Wehrens XH, Cooper TA. PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1. J Clin Invest. 2009;119(12):3797–806. https://doi.org/10.1172/JCI37976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Furling D, Doucet G, Langlois MA, Timchenko L, Belanger E, Cossette L, et al. Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions. Gene Ther. 2003;10(9):795–802. https://doi.org/10.1038/sj.gt.3301955.

    Article  CAS  PubMed  Google Scholar 

  23. Langlois MA, Boniface C, Wang G, Alluin J, Salvaterra PM, Puymirat J, et al. Cytoplasmic and nuclear retained DMPK mRNAs are targets for RNA interference in myotonic dystrophy cells. J Biol Chem. 2005;280(17):16949–54. https://doi.org/10.1074/jbc.M501591200.

    Article  CAS  PubMed  Google Scholar 

  24. Nakamori M, Gourdon G, Thornton CA. Stabilization of expanded (CTG)*(CAG) repeats by antisense oligonucleotides. Mol Ther. 2011;19(12):2222–7. https://doi.org/10.1038/mt.2011.191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mankodi A, Logigian E, Callahan L, McClain C, White R, Henderson D, et al. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science. 2000;289(5485):1769–73.

    Article  CAS  Google Scholar 

  26. 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 

  27. 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 

  28. Warf MB, Nakamori M, Matthys CM, Thornton CA, Berglund JA. Pentamidine reverses the splicing defects associated with myotonic dystrophy. Proc Natl Acad Sci U S A. 2009;106(44):18551–6. https://doi.org/10.1073/pnas.0903234106.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Parkesh R, Childs-Disney JL, Nakamori M, Kumar A, Wang E, Wang T, et al. Design of a bioactive small molecule that Targets the myotonic dystrophy type 1 RNA via an RNA motif-ligand database and chemical similarity searching. J Am Chem Soc. 2012;134(10):4731–42. https://doi.org/10.1021/ja210088v.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Childs-Disney JL, Parkesh R, Nakamori M, Thornton CA, Disney MD. Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy type 1. ACS Chem Biol. 2012;7(12):1984–93. https://doi.org/10.1021/cb3001606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ofori LO, Hoskins J, Nakamori M, Thornton CA, Miller BL. From dynamic combinatorial ‘hit’ to lead: in vitro and in vivo activity of compounds targeting the pathogenic RNAs that cause myotonic dystrophy. Nucleic Acids Res. 2012;40(13):6380–90. https://doi.org/10.1093/nar/gks298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Coonrod LA, Nakamori M, Wang W, Carrell S, Hilton CL, Bodner MJ, et al. Reducing levels of toxic RNA with small molecules. ACS Chem Biol. 2013;8(11):2528–37. https://doi.org/10.1021/cb400431f.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Siboni RB, Bodner MJ, Khalifa MM, Docter AG, Choi JY, Nakamori M, et al. Biological efficacy and toxicity of diamidines in myotonic dystrophy type 1 models. J Med Chem. 2015;58(15):5770–80. https://doi.org/10.1021/acs.jmedchem.5b00356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Siboni RB, Nakamori M, Wagner SD, Struck AJ, Coonrod LA, Harriott SA, et al. Actinomycin D specifically reduces expanded CUG repeat RNA in myotonic dystrophy models. Cell Rep. 2015;13(11):2386–94. https://doi.org/10.1016/j.celrep.2015.11.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nakamori M, Taylor K, Mochizuki H, Sobczak K, Takahashi MP. Oral administration of erythromycin decreases RNA toxicity in myotonic dystrophy. Ann Clin Transl Neurol. 2016;3(1):42–54. https://doi.org/10.1002/acn3.271.

    Article  CAS  PubMed  Google Scholar 

  36. Nakamori M, Pearson CE, Thornton CA. Bidirectional transcription stimulates expansion and contraction of expanded (CTG)•(CAG) repeats. Hum Mol Genet. 2011;20(3):580–8. https://doi.org/10.1093/hmg/ddq501.

    Article  CAS  PubMed  Google Scholar 

  37. Nakamori M, Sobczak K, Moxley RT III, Thornton CA. Scaled-down genetic analysis of myotonic dystrophy type 1 and type 2. Neuromuscul Disord. 2009;19(11):759–62. https://doi.org/10.1016/j.nmd.2009.07.012.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Gomes-Pereira M, Monckton DG. Chemically induced increases and decreases in the rate of expansion of a CAG*CTG triplet repeat. Nucleic Acids Res. 2004;32(9):2865–72. https://doi.org/10.1093/nar/gkh612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Heatwole C, Bode R, Johnson NE, Dekdebrun J, Dilek N, Eichinger K, et al. Myotonic dystrophy health index: correlations with clinical tests and patient function. Muscle Nerve. 2016;53(2):183–90. https://doi.org/10.1002/mus.24725.

    Article  PubMed  Google Scholar 

  40. Garcia-Lopez A, et al. In vivo discovery of a peptide that prevents CUG-RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models. Proc Natl Acad Sci U S A. 2011;108:11866–71.

    Article  CAS  Google Scholar 

  41. Jones K, et al. GSK3β mediates muscle pathology in myotonic dystrophy. J Clin Invest. 2012;122:4461–72.

    Article  CAS  Google Scholar 

  42. Oana K, et al. Manumycin A corrects aberrant splicing of Clcn1 in myotonic dystrophy type 1 (DM1) mice. Sci Rep. 2142;2013:3.

    Google Scholar 

  43. Herrendorff R, et al. Identification of plant-derived alkaloids with therapeutic potential for myotonic dystrophy type I. J Biol Chem. 2016;291:17165–77.

    Article  CAS  Google Scholar 

  44. Chen G, et al. Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy. Sci Rep. 2016;6:25317.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan

    Masayuki Nakamori

Authors
  1. Masayuki Nakamori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masayuki Nakamori .

Editor information

Editors and Affiliations

  1. Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka, Japan

    Masanori P. Takahashi

  2. Department of Neurology, National Hospital Organization Toneyama National Hospital, Osaka, Japan

    Tsuyoshi Matsumura

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Nakamori, M. (2018). Therapeutic Development in Myotonic Dystrophy. In: Takahashi, M., Matsumura, T. (eds) Myotonic Dystrophy. Springer, Singapore. https://doi.org/10.1007/978-981-13-0508-5_13

Download citation

  • DOI: https://doi.org/10.1007/978-981-13-0508-5_13

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-13-0507-8

  • Online ISBN: 978-981-13-0508-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation