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Gene Therapy and Gene Editing for Myotonic Dystrophy

  • Marinee ChuahEmail author
  • Yoke Chin Chai
  • Sumitava Dastidar
  • Thierry VandenDriesscheEmail author
Chapter

Abstract

Myotonic dystrophy is one of the most common dominant neuromuscular disorders that results in muscle dysfunction. Myotonic dystrophy type 1 (DM1) or Steinert’s disease is caused by an expanded CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene, whereas myotonic dystrophy type (DM2) is caused by expanded CCTG repeats in the first intron of the CCHC-type zinc finger, nucleic acid-binding protein (CNBP) gene. The clinical manifestations worsen with each generation (anticipation) consistent with an expansion of the repeats. The tri- or tetranucleotide repeat expansion results in gain-of-function pathogenic RNAs which are retained in the nuclei and sequester RNA-binding proteins such as MBNL and CUGBP that interfere with splicing. Unfortunately, there is currently no cure available for these dominant neuromuscular diseases. Nevertheless, some promising therapeutic strategies have been developed that are aimed at directly tackling the genetic cause of the disease. In particular, antisense oligonucleotide technologies, gene therapy, and gene editing or small molecules are being explored. Recently, a phase 1/2a clinical trial has been completed that is based on the premise of promoting RNase-H-mediated degradation of the expanded CUG transcripts using antisense oligonucleotides. In this review, we summarize the current progress on different cellular and animal models as well as various therapeutic strategies for DM with specific emphasis on gene therapy and gene editing approaches using TALENs and CRISPR/Cas9. Lastly, translational challenges and future promising therapeutic avenues are discussed.

Keywords

Myotonic dystrophy Steinert DM1 DM2 DMPK CNBP Trinucleotide repeat Gene therapy Gene editing Antisense oligonucleotides CRISPR/Cas9 TALEN iPS Muscle Heart 

Notes

Acknowledgments

Some of the research described herein was conducted in the laboratories of TV and MC. This research was supported by grants from the Research Foundation of Flanders (FWO), Association Française contre les Myopathies (AFM), Scientific Fund Willy Gepts (WFWG, VUB), and King Boudewijn Foundation—Walter Pyleman Fund. YCC is supported by the IOF-GEAR grant (Vrije Universiteit Brussel); SD is supported by the PhD studentship of the Willy Gepts Fund (Wetenschappelijk Fonds Willy Gepts—Vrije Universiteit Brussel) and the King Boudewijn Foundation Walter Pyleman Fund. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 667751 (MYOCURE).

Conflicts of Interest

The authors have no conflicts of interest to report.

References

  1. 1.
    Musova Z, Mazanec R, Krepelova A, Ehler E, Vales J, Jaklova R, Prochazka T, Koukal P, Marikova T, Kraus J, Havlovicova M, Sedlacek Z (2009) Highly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene. Am J Med Genet A 149A(7):1365–1374.  https://doi.org/10.1002/ajmg.a.32987 CrossRefPubMedGoogle Scholar
  2. 2.
    Udd B, Krahe R (2012) The myotonic dystrophies: molecular, clinical, and therapeutic challenges. Lancet Neurol 11(10):891–905.  https://doi.org/10.1016/S1474-4422(12)70204-1 CrossRefPubMedGoogle Scholar
  3. 3.
    Mathieu J, De Braekeleer M, Prevost C (1990) Genealogical reconstruction of myotonic dystrophy in the Saguenay-Lac-Saint-Jean area (Quebec, Canada). Neurology 40(5):839–842CrossRefGoogle Scholar
  4. 4.
    Fu YH, Pizzuti A, Fenwick RG Jr, King J, Rajnarayan S, Dunne PW, Dubel J, Nasser GA, Ashizawa T, de Jong P et al (1992) An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255(5049):1256–1258CrossRefGoogle Scholar
  5. 5.
    Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C, Narang M, Barcelo J, O’Hoy K et al (1992) Myotonic dystrophy mutation: an unstable CTG repeat in the 3’ untranslated region of the gene. Science 255(5049):1253–1255CrossRefGoogle Scholar
  6. 6.
    Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T et al (1992) 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 68(4):799–808CrossRefGoogle Scholar
  7. 7.
    Savic Pavicevic D, Miladinovic J, Brkusanin M, Svikovic S, Djurica S, Brajuskovic G, Romac S (2013) Molecular genetics and genetic testing in myotonic dystrophy type 1. Biomed Res Int 2013:391821.  https://doi.org/10.1155/2013/391821 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Groh WJ, Groh MR, Shen C, Monckton DG, Bodkin CL, Pascuzzi RM (2011) Survival and CTG repeat expansion in adults with myotonic dystrophy type 1. Muscle Nerve 43(5):648–651.  https://doi.org/10.1002/mus.21934 CrossRefPubMedGoogle Scholar
  9. 9.
    Barbe L, Lanni S, Lopez-Castel A, Franck S, Spits C, Keymolen K, Seneca S, Tome S, Miron I, Letourneau J, Liang M, Choufani S, Weksberg R, Wilson MD, Sedlacek Z, Gagnon C, Musova Z, Chitayat D, Shannon P, Mathieu J, Sermon K, Pearson CE (2017) CpG methylation, a parent-of-origin effect for maternal-biased transmission of congenital myotonic dystrophy. Am J Hum Genet 100(3):488–505.  https://doi.org/10.1016/j.ajhg.2017.01.033 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Harper PS, Harley HG, Reardon W, Shaw DJ (1992) Anticipation in myotonic dystrophy: new light on an old problem. Am J Hum Genet 51(1):10–16PubMedPubMedCentralGoogle Scholar
  11. 11.
    Lavedan C, Hofmann-Radvanyi H, Shelbourne P, Rabes JP, Duros C, Savoy D, Dehaupas I, Luce S, Johnson K, Junien C (1993) Myotonic dystrophy: size- and sex-dependent dynamics of CTG meiotic instability, and somatic mosaicism. Am J Hum Genet 52(5):875–883PubMedPubMedCentralGoogle Scholar
  12. 12.
    Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LP (2001) Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293(5531):864–867.  https://doi.org/10.1126/science.1062125 CrossRefPubMedGoogle Scholar
  13. 13.
    Liquori CL, Ikeda Y, Weatherspoon M, Ricker K, Schoser BG, Dalton JC, Day JW, Ranum LP (2003) Myotonic dystrophy type 2: human founder haplotype and evolutionary conservation of the repeat tract. Am J Hum Genet 73(4):849–862.  https://doi.org/10.1086/378720 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kurosaki T, Ueda S, Ishida T, Abe K, Ohno K, Matsuura T (2012) The unstable CCTG repeat responsible for myotonic dystrophy type 2 originates from an AluSx element insertion into an early primate genome. PLoS One 7(6):e38379.  https://doi.org/10.1371/journal.pone.0038379 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Guo P, Lam SL (2015) New insights into the genetic instability in CCTG repeats. FEBS Lett 589(20 Pt B):3058–3063.  https://doi.org/10.1016/j.febslet.2015.09.007 CrossRefPubMedGoogle Scholar
  16. 16.
    Suominen T, Bachinski LL, Auvinen S, Hackman P, Baggerly KA, Angelini C, Peltonen L, Krahe R, Udd B (2011) Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland. Eur J Hum Genet 19(7):776–782.  https://doi.org/10.1038/ejhg.2011.23 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Harper PS (2001) The genetic basis of myotonic dystrophy. In: Harper PS (ed) Myotonic dystrophy, 3rd edn. W.B. Saunders, London, pp 307–363Google Scholar
  18. 18.
    Bellini M, Biagi S, Stasi C, Costa F, Mumolo MG, Ricchiuti A, Marchi S (2006) Gastrointestinal manifestations in myotonic muscular dystrophy. World J Gastroenterol 12(12):1821–1828CrossRefGoogle Scholar
  19. 19.
    Meola G, Cardani R (2017) Myotonic dystrophy type 2 and modifier genes: an update on clinical and pathomolecular aspects. Neurol Sci 38(4):535–546.  https://doi.org/10.1007/s10072-016-2805-5 CrossRefPubMedGoogle Scholar
  20. 20.
    Day JW, Ranum LP (2005) RNA pathogenesis of the myotonic dystrophies. Neuromuscul Disord 15(1):5–16.  https://doi.org/10.1016/j.nmd.2004.09.012 CrossRefPubMedGoogle Scholar
  21. 21.
    Renna LV, Cardani R, Botta A, Rossi G, Fossati B, Costa E, Meola G (2014) Premature senescence in primary muscle cultures of myotonic dystrophy type 2 is not associated with p16 induction. Eur J Histochem 58(4):2444.  https://doi.org/10.4081/ejh.2014.2444 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bigot A, Klein AF, Gasnier E, Jacquemin V, Ravassard P, Butler-Browne G, Mouly V, Furling D (2009) Large CTG repeats trigger p16-dependent premature senescence in myotonic dystrophy type 1 muscle precursor cells. Am J Pathol 174(4):1435–1442.  https://doi.org/10.2353/ajpath.2009.080560 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Arsenault ME, Prevost C, Lescault A, Laberge C, Puymirat J, Mathieu J (2006) Clinical characteristics of myotonic dystrophy type 1 patients with small CTG expansions. Neurology 66(8):1248–1250.  https://doi.org/10.1212/01.wnl.0000208513.48550.08 CrossRefPubMedGoogle Scholar
  24. 24.
    Serra L, Mancini M, Silvestri G, Petrucci A, Masciullo M, Spano B, Torso M, Mastropasqua C, Giacanelli M, Caltagirone C, Cercignani M, Meola G, Bozzali M (2016) Brain connectomics’ modification to clarify motor and nonmotor features of myotonic dystrophy type 1. Neural Plast 2016:2696085.  https://doi.org/10.1155/2016/2696085 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Denis JA, Gauthier M, Rachdi L, Aubert S, Giraud-Triboult K, Poydenot P, Benchoua A, Champon B, Maury Y, Baldeschi C, Scharfmann R, Pietu G, Peschanski M, Martinat C (2013) mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by myotonic dystrophy type 1. J Cell Sci 126(Pt 8):1763–1772.  https://doi.org/10.1242/jcs.116285 CrossRefPubMedGoogle Scholar
  26. 26.
    Ho G, Cardamone M, Farrar M (2015) Congenital and childhood myotonic dystrophy: current aspects of disease and future directions. World J Clin Pediatr 4(4):66–80.  https://doi.org/10.5409/wjcp.v4.i4.66 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Davis BM, McCurrach ME, Taneja KL, Singer RH, Housman DE (1997) Expansion of a CUG trinucleotide repeat in the 3’ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. Proc Natl Acad Sci U S A 94(14):7388–7393CrossRefGoogle Scholar
  28. 28.
    Taneja KL, McCurrach M, Schalling M, Housman D, Singer RH (1995) Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol 128(6):995–1002CrossRefGoogle Scholar
  29. 29.
    Mankodi A, Logigian E, Callahan L, McClain C, White R, Henderson D, Krym M, Thornton CA (2000) Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289(5485):1769–1773CrossRefGoogle Scholar
  30. 30.
    Seznec H, Agbulut O, Sergeant N, Savouret C, Ghestem A, Tabti N, Willer JC, Ourth L, Duros C, Brisson E, Fouquet C, Butler-Browne G, Delacourte A, Junien C, Gourdon G (2001) Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities. Hum Mol Genet 10(23):2717–2726CrossRefGoogle Scholar
  31. 31.
    Michalowski S, Miller JW, Urbinati CR, Paliouras M, Swanson MS, Griffith J (1999) Visualization of double-stranded RNAs from the myotonic dystrophy protein kinase gene and interactions with CUG-binding protein. Nucleic Acids Res 27(17):3534–3542CrossRefGoogle Scholar
  32. 32.
    Mooers BH, Logue JS, Berglund JA (2005) The structural basis of myotonic dystrophy from the crystal structure of CUG repeats. Proc Natl Acad Sci U S A 102(46):16626–16631.  https://doi.org/10.1073/pnas.0505873102 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS (2000) Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J 19(17):4439–4448.  https://doi.org/10.1093/emboj/19.17.4439 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Tian B, White RJ, Xia T, Welle S, Turner DH, Mathews MB, Thornton CA (2000) Expanded CUG repeat RNAs form hairpins that activate the double-stranded RNA-dependent protein kinase PKR. RNA 6(1):79–87CrossRefGoogle Scholar
  35. 35.
    Kanadia RN, Johnstone KA, Mankodi A, Lungu C, Thornton CA, Esson D, Timmers AM, Hauswirth WW, Swanson MS (2003) A muscleblind knockout model for myotonic dystrophy. Science 302(5652):1978–1980.  https://doi.org/10.1126/science.1088583 CrossRefPubMedGoogle Scholar
  36. 36.
    Charizanis K, Lee KY, Batra R, Goodwin M, Zhang C, Yuan Y, Shiue L, Cline M, Scotti MM, Xia G, Kumar A, Ashizawa T, Clark HB, Kimura T, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Gomes-Pereira M, Gourdon G, Sakai N, Nishino S, Foster TC, Ares M Jr, Darnell RB, Swanson MS (2012) Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy. Neuron 75(3):437–450.  https://doi.org/10.1016/j.neuron.2012.05.029 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Hao M, Akrami K, Wei K, De Diego C, Che N, Ku JH, Tidball J, Graves MC, Shieh PB, Chen F (2008) Muscleblind-like 2 (Mbnl2) -deficient mice as a model for myotonic dystrophy. Dev Dyn 237(2):403–410.  https://doi.org/10.1002/dvdy.21428 CrossRefPubMedGoogle Scholar
  38. 38.
    Lee KY, Li M, Manchanda M, Batra R, Charizanis K, Mohan A, Warren SA, Chamberlain CM, Finn D, Hong H, Ashraf H, Kasahara H, Ranum LP, Swanson MS (2013) Compound loss of muscleblind-like function in myotonic dystrophy. EMBO Mol Med 5(12):1887–1900.  https://doi.org/10.1002/emmm.201303275 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kalsotra A, Xiao X, Ward AJ, Castle JC, Johnson JM, Burge CB, Cooper TA (2008) A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc Natl Acad Sci U S A 105(51):20333–20338.  https://doi.org/10.1073/pnas.0809045105 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Konieczny P, Stepniak-Konieczna E, Sobczak K (2015) MBNL proteins and their target RNAs, interaction and splicing regulation. Nucleic Acids Res 42(17):10873–10887.  https://doi.org/10.1093/nar/gku767 CrossRefGoogle Scholar
  41. 41.
    Kanadia RN, Urbinati CR, Crusselle VJ, Luo D, Lee YJ, Harrison JK, Oh SP, Swanson MS (2003) Developmental expression of mouse muscleblind genes Mbnl1, Mbnl2 and Mbnl3. Gene Expr Patterns 3(4):459–462CrossRefGoogle Scholar
  42. 42.
    Lin X, Miller JW, Mankodi A, Kanadia RN, Yuan Y, Moxley RT, Swanson MS, Thornton CA (2006) Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum Mol Genet 15(13):2087–2097.  https://doi.org/10.1093/hmg/ddl132 CrossRefPubMedGoogle Scholar
  43. 43.
    Dansithong W, Paul S, Comai L, Reddy S (2005) MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1. J Biol Chem 280(7):5773–5780.  https://doi.org/10.1074/jbc.M410781200 CrossRefPubMedGoogle Scholar
  44. 44.
    Kino Y, Washizu C, Kurosawa M, Oma Y, Hattori N, Ishiura S, Nukina N (2015) Nuclear localization of MBNL1: splicing-mediated autoregulation and repression of repeat-derived aberrant proteins. Hum Mol Genet 24(3):740–756.  https://doi.org/10.1093/hmg/ddu492 CrossRefPubMedGoogle Scholar
  45. 45.
    Michel L, Huguet-Lachon A, Gourdon G (2015) Sense and antisense DMPK RNA foci accumulate in DM1 tissues during development. PLoS One 10(9):e0137620.  https://doi.org/10.1371/journal.pone.0137620 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Iyer D, Belaguli N, Fluck M, Rowan BG, Wei L, Weigel NL, Booth FW, Epstein HF, Schwartz RJ, Balasubramanyam A (2003) Novel phosphorylation target in the serum response factor MADS box regulates alpha-actin transcription. Biochemistry 42(24):7477–7486.  https://doi.org/10.1021/bi030045n CrossRefPubMedGoogle Scholar
  47. 47.
    Lee MY, Park C, Ha SE, Park PJ, Berent RM, Jorgensen BG, Corrigan RD, Grainger N, Blair PJ, Slivano OJ, Miano JM, Ward SM, Smith TK, Sanders KM, Ro S (2017) Serum response factor regulates smooth muscle contractility via myotonic dystrophy protein kinases and L-type calcium channels. PLoS One 12(2):e0171262.  https://doi.org/10.1371/journal.pone.0171262 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Klesert TR, Cho DH, Clark JI, Maylie J, Adelman J, Snider L, Yuen EC, Soriano P, Tapscott SJ (2000) Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy. Nat Genet 25(1):105–109.  https://doi.org/10.1038/75490 CrossRefPubMedGoogle Scholar
  49. 49.
    Sarkar PS, Appukuttan B, Han J, Ito Y, Ai C, Tsai W, Chai Y, Stout JT, Reddy S (2000) Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts. Nat Genet 25(1):110–114.  https://doi.org/10.1038/75500 CrossRefPubMedGoogle Scholar
  50. 50.
    Wakimoto H, Maguire CT, Sherwood MC, Vargas MM, Sarkar PS, Han J, Reddy S, Berul CI (2002) Characterization of cardiac conduction system abnormalities in mice with targeted disruption of Six5 gene. J Interv Card Electrophysiol 7(2):127–135CrossRefGoogle Scholar
  51. 51.
    Personius KE, Nautiyal J, Reddy S (2005) Myotonia and muscle contractile properties in mice with SIX5 deficiency. Muscle Nerve 31(4):503–505.  https://doi.org/10.1002/mus.20239 CrossRefPubMedGoogle Scholar
  52. 52.
    Rhodes JD, Lott MC, Russell SL, Moulton V, Sanderson J, Wormstone IM, Broadway DC (2012) Activation of the innate immune response and interferon signalling in myotonic dystrophy type 1 and type 2 cataracts. Hum Mol Genet 21(4):852–862.  https://doi.org/10.1093/hmg/ddr515 CrossRefPubMedGoogle Scholar
  53. 53.
    Nakamori M, Sobczak K, Puwanant A, Welle S, Eichinger K, Pandya S, Dekdebrun J, Heatwole CR, McDermott MP, Chen T, Cline M, Tawil R, Osborne RJ, Wheeler TM, Swanson MS, Moxley RT 3rd, Thornton CA (2013) Splicing biomarkers of disease severity in myotonic dystrophy. Ann Neurol 74(6):862–872.  https://doi.org/10.1002/ana.23992 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Charlet BN, Savkur RS, Singh G, Philips AV, Grice EA, Cooper TA (2002) Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell 10(1):45–53CrossRefGoogle Scholar
  55. 55.
    Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, Moxley RT, Cannon SC, Thornton CA (2002) Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 10(1):35–44CrossRefGoogle Scholar
  56. 56.
    Fugier C, Klein AF, Hammer C, Vassilopoulos S, Ivarsson Y, Toussaint A, Tosch V, Vignaud A, Ferry A, Messaddeq N, Kokunai Y, Tsuburaya R, de la Grange P, Dembele D, Francois V, Precigout G, Boulade-Ladame C, Hummel MC, de Munain AL, Sergeant N, Laquerriere A, Thibault C, Deryckere F, Auboeuf D, Garcia L, Zimmermann P, Udd B, Schoser B, Takahashi MP, Nishino I, Bassez G, Laporte J, Furling D, Charlet-Berguerand N (2011) Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. Nat Med 17(6):720–725.  https://doi.org/10.1038/nm.2374 CrossRefPubMedGoogle Scholar
  57. 57.
    Tang ZZ, Yarotskyy V, Wei L, Sobczak K, Nakamori M, Eichinger K, Moxley RT, Dirksen RT, Thornton CA (2012) Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of Ca(V)1.1 calcium channel. Hum Mol Genet 21(6):1312–1324.  https://doi.org/10.1093/hmg/ddr568 CrossRefPubMedGoogle Scholar
  58. 58.
    Rau F, Lainé J, Ramanoudjame L, Ferry A, Arandel L, Delalande O, Jollet A, Dingli F, Lee K-Y, Peccate C, Lorain S, Kabashi E, Athanasopoulos T, Koo T, Loew D, Swanson MS, Le Rumeur E, Dickson G, Allamand V, Marie J, Furling D (2015) Abnormal splicing switch of DMD’s penultimate exon compromises muscle fiber maintenance in myotonic dystrophy. Nat Commun 6:7205CrossRefGoogle Scholar
  59. 59.
    Savkur RS, Philips AV, Cooper TA (2001) Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet 29(1):40–47.  https://doi.org/10.1038/ng704 CrossRefPubMedGoogle Scholar
  60. 60.
    Sergeant N, Sablonniere B, Schraen-Maschke S, Ghestem A, Maurage CA, Wattez A, Vermersch P, Delacourte A (2001) Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum Mol Genet 10(19):2143–2155CrossRefGoogle Scholar
  61. 61.
    Rau F, Freyermuth F, Fugier C, Villemin JP, Fischer MC, Jost B, Dembele D, Gourdon G, Nicole A, Duboc D, Wahbi K, Day JW, Fujimura H, Takahashi MP, Auboeuf D, Dreumont N, Furling D, Charlet-Berguerand N (2011) Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. Nat Struct Mol Biol 18(7):840–845.  https://doi.org/10.1038/nsmb.2067 CrossRefPubMedGoogle Scholar
  62. 62.
    Wang GS, Kuyumcu-Martinez MN, Sarma S, Mathur N, Wehrens XH, Cooper TA (2009) PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1. J Clin Invest 119(12):3797–3806.  https://doi.org/10.1172/JCI37976 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Kuyumcu-Martinez NM, Wang GS, Cooper TA (2007) Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol Cell 28(1):68–78.  https://doi.org/10.1016/j.molcel.2007.07.027 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Dansithong W, Jog SP, Paul S, Mohammadzadeh R, Tring S, Kwok Y, Fry RC, Marjoram P, Comai L, Reddy S (2011) RNA steady-state defects in myotonic dystrophy are linked to nuclear exclusion of SHARP. EMBO Rep 12(7):735–742.  https://doi.org/10.1038/embor.2011.86 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Gladman JT, Yadava RS, Mandal M, Yu Q, Kim YK, Mahadevan MS (2015) NKX2-5, a modifier of skeletal muscle pathology due to RNA toxicity. Hum Mol Genet 24(1):251–264.  https://doi.org/10.1093/hmg/ddu443 CrossRefPubMedGoogle Scholar
  66. 66.
    Laurent FX, Sureau A, Klein AF, Trouslard F, Gasnier E, Furling D, Marie J (2012) New function for the RNA helicase p68/DDX5 as a modifier of MBNL1 activity on expanded CUG repeats. Nucleic Acids Res 40(7):3159–3171.  https://doi.org/10.1093/nar/gkr1228 CrossRefPubMedGoogle Scholar
  67. 67.
    Ravel-Chapuis A, Belanger G, Yadava RS, Mahadevan MS, DesGroseillers L, Cote J, Jasmin BJ (2012) The RNA-binding protein Staufen1 is increased in DM1 skeletal muscle and promotes alternative pre-mRNA splicing. J Cell Biol 196(6):699–712.  https://doi.org/10.1083/jcb.201108113 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Yadava RS, Frenzel-McCardell CD, Yu Q, Srinivasan V, Tucker AL, Puymirat J, Thornton CA, Prall OW, Harvey RP, Mahadevan MS (2008) RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression. Nat Genet 40(1):61–68.  https://doi.org/10.1038/ng.2007.28 CrossRefPubMedGoogle Scholar
  69. 69.
    Bondy-Chorney E, Crawford Parks TE, Ravel-Chapuis A, Klinck R, Rocheleau L, Pelchat M, Chabot B, Jasmin BJ, Cote J (2016) Staufen1 regulates multiple alternative splicing events either positively or negatively in DM1 indicating its role as a disease modifier. PLoS Genet 12(1):e1005827.  https://doi.org/10.1371/journal.pgen.1005827 CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Du H, Cline MS, Osborne RJ, Tuttle DL, Clark TA, Donohue JP, Hall MP, Shiue L, Swanson MS, Thornton CA, Ares M Jr (2010) Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nat Struct Mol Biol 17(2):187–193.  https://doi.org/10.1038/nsmb.1720 CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Osborne RJ, Lin X, Welle S, Sobczak K, O’Rourke JR, Swanson MS, Thornton CA (2009) Transcriptional and post-transcriptional impact of toxic RNA in myotonic dystrophy. Hum Mol Genet 18(8):1471–1481.  https://doi.org/10.1093/hmg/ddp058 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Perfetti A, Greco S, Fasanaro P, Bugiardini E, Cardani R, Garcia-Manteiga JM, Riba M, Cittaro D, Stupka E, Meola G, Martelli F (2014) Genome wide identification of aberrant alternative splicing events in myotonic dystrophy type 2. PLoS One 9(4):e93983.  https://doi.org/10.1371/journal.pone.0093983 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Bachinski LL, Baggerly KA, Neubauer VL, Nixon TJ, Raheem O, Sirito M, Unruh AK, Zhang J, Nagarajan L, Timchenko LT, Bassez G, Eymard B, Gamez J, Ashizawa T, Mendell JR, Udd B, Krahe R (2014) Most expression and splicing changes in myotonic dystrophy type 1 and type 2 skeletal muscle are shared with other muscular dystrophies. Neuromuscul Disord 24(3):227–240.  https://doi.org/10.1016/j.nmd.2013.11.001 CrossRefPubMedGoogle Scholar
  74. 74.
    An MC, Zhang N, Scott G, Montoro D, Wittkop T, Mooney S, Melov S, Ellerby LM (2012) Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells. Cell Stem Cell 11(2):253–263.  https://doi.org/10.1016/j.stem.2012.04.026 CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Mittelman D, Moye C, Morton J, Sykoudis K, Lin Y, Carroll D, Wilson JH (2009) Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells. Proc Natl Acad Sci U S A 106(24):9607–9612.  https://doi.org/10.1073/pnas.0902420106 CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Olsen PA, Solhaug A, Booth JA, Gelazauskaite M, Krauss S (2009) Cellular responses to targeted genomic sequence modification using single-stranded oligonucleotides and zinc-finger nucleases. DNA Repair (Amst) 8(3):298–308.  https://doi.org/10.1016/j.dnarep.2008.11.011 CrossRefGoogle Scholar
  77. 77.
    Richard GF, Viterbo D, Khanna V, Mosbach V, Castelain L, Dujon B (2014) Highly specific contractions of a single CAG/CTG trinucleotide repeat by TALEN in yeast. PLoS One 9(4):e95611.  https://doi.org/10.1371/journal.pone.0095611 CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Gao Y, Guo X, Santostefano K, Wang Y, Reid T, Zeng D, Terada N, Ashizawa T, Xia G (2016) Genome therapy of myotonic dystrophy type 1 iPS cells for development of autologous stem cell therapy. Mol Ther 24(8):1378–1387.  https://doi.org/10.1038/mt.2016.97 CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Xia G, Gao Y, Jin S, Subramony S, Terada N, Ranum LP, Swanson MS, Ashizawa T (2015) Genome modification leads to phenotype reversal in human myotonic dystrophy type 1 iPS-cell derived neural stem cells. Stem Cells 33(6):1829–1838.  https://doi.org/10.1002/stem.1970 CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    van Agtmaal EL, Andre LM, Willemse M, Cumming SA, van Kessel ID, van den Broek WJ, Gourdon G, Furling D, Mouly V, Monckton DG, Wansink DG, Wieringa B (2017) CRISPR/Cas9-induced (CTGCAG)n repeat instability in the myotonic dystrophy type 1 locus: implications for therapeutic genome editing. Mol Ther 25(1):24–43.  https://doi.org/10.1016/j.ymthe.2016.10.014 CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Maeder ML, Linder SJ, Cascio VM, Fu Y, Ho QH, Joung JK (2013) CRISPR RNA-guided activation of endogenous human genes. Nat Methods 10(10):977–979.  https://doi.org/10.1038/nmeth.2598 CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Furling D, Coiffier L, Mouly V, Barbet JP, St Guily JL, Taneja K, Gourdon G, Junien C, Butler-Browne GS (2001) Defective satellite cells in congenital myotonic dystrophy. Hum Mol Genet 10(19):2079–2087CrossRefGoogle Scholar
  83. 83.
    Ketley A, Chen CZ, Li X, Arya S, Robinson TE, Granados-Riveron J, Udosen I, Morris GE, Holt I, Furling D, Chaouch S, Haworth B, Southall N, Shinn P, Zheng W, Austin CP, Hayes CJ, Brook JD (2014) High-content screening identifies small molecules that remove nuclear foci, affect MBNL distribution and CELF1 protein levels via a PKC-independent pathway in myotonic dystrophy cell lines. Hum Mol Genet 23(6):1551–1562.  https://doi.org/10.1093/hmg/ddt542 CrossRefPubMedGoogle Scholar
  84. 84.
    Gonzalez-Barriga A, Mulders SA, van de Giessen J, Hooijer JD, Bijl S, van Kessel ID, van Beers J, van Deutekom JC, Fransen JA, Wieringa B, Wansink DG (2013) Design and analysis of effects of triplet repeat oligonucleotides in cell models for myotonic dystrophy. Mol Ther Nucleic Acids 2:e81.  https://doi.org/10.1038/mtna.2013.9 CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Hernandez-Hernandez O, Guiraud-Dogan C, Sicot G, Huguet A, Luilier S, Steidl E, Saenger S, Marciniak E, Obriot H, Chevarin C, Nicole A, Revillod L, Charizanis K, Lee KY, Suzuki Y, Kimura T, Matsuura T, Cisneros B, Swanson MS, Trovero F, Buisson B, Bizot JC, Hamon M, Humez S, Bassez G, Metzger F, Buee L, Munnich A, Sergeant N, Gourdon G, Gomes-Pereira M (2013) Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour. Brain 136(Pt 3):957–970.  https://doi.org/10.1093/brain/aws367 CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Hoskins JW, Ofori LO, Chen CZ, Kumar A, Sobczak K, Nakamori M, Southall N, Patnaik S, Marugan JJ, Zheng W, Austin CP, Disney MD, Miller BL, Thornton CA (2014) Lomofungin and dilomofungin: inhibitors of MBNL1-CUG RNA binding with distinct cellular effects. Nucleic Acids Res 42(10):6591–6602.  https://doi.org/10.1093/nar/gku275 CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Jones K, Wei C, Iakova P, Bugiardini E, Schneider-Gold C, Meola G, Woodgett J, Killian J, Timchenko NA, Timchenko LT (2012) GSK3beta mediates muscle pathology in myotonic dystrophy. J Clin Invest 122(12):4461–4472.  https://doi.org/10.1172/JCI64081 CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Arandel L, Polay-Espinosa M, Matloka M, Bazinet A, De Dea Diniz D, Naouar N, Rau F, Jollet A, Edom-Vovard F, Mamchaoui K, Tarnopolsky M, Puymirat J, Battail C, Boland A, Deleuze JF, Mouly V, Klein AF, Furling D (2017) Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds. Dis Model Mech 10(4):487–497.  https://doi.org/10.1242/dmm.027367 CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Du J, Campau E, Soragni E, Jespersen C, Gottesfeld JM (2013) Length-dependent CTG.CAG triplet-repeat expansion in myotonic dystrophy patient-derived induced pluripotent stem cells. Hum Mol Genet 22(25):5276–5287.  https://doi.org/10.1093/hmg/ddt386 CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Gomes-Pereira M, Cooper TA, Gourdon G (2011) Myotonic dystrophy mouse models: towards rational therapy development. Trends Mol Med 17(9):506–517.  https://doi.org/10.1016/j.molmed.2011.05.004 CrossRefPubMedGoogle Scholar
  91. 91.
    Huguet A, Medja F, Nicole A, Vignaud A, Guiraud-Dogan C, Ferry A, Decostre V, Hogrel JY, Metzger F, Hoeflich A, Baraibar M, Gomes-Pereira M, Puymirat J, Bassez G, Furling D, Munnich A, Gourdon G (2012) Molecular, physiological, and motor performance defects in DMSXL mice carrying >1,000 CTG repeats from the human DM1 locus. PLoS Genet 8(11):e1003043.  https://doi.org/10.1371/journal.pgen.1003043 CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Vignaud A, Ferry A, Huguet A, Baraibar M, Trollet C, Hyzewicz J, Butler-Browne G, Puymirat J, Gourdon G, Furling D (2010) Progressive skeletal muscle weakness in transgenic mice expressing CTG expansions is associated with the activation of the ubiquitin-proteasome pathway. Neuromuscul Disord 20(5):319–325.  https://doi.org/10.1016/j.nmd.2010.03.006 CrossRefPubMedGoogle Scholar
  93. 93.
    Gomes-Pereira M, Foiry L, Nicole A, Huguet A, Junien C, Munnich A, Gourdon G (2007) CTG trinucleotide repeat “big jumps”: large expansions, small mice. PLoS Genet 3(4):e52.  https://doi.org/10.1371/journal.pgen.0030052 CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Wang GS, Kearney DL, De Biasi M, Taffet G, Cooper TA (2007) Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. J Clin Invest 117(10):2802–2811.  https://doi.org/10.1172/JCI32308 CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Salisbury E, Schoser B, Schneider-Gold C, Wang GL, Huichalaf C, Jin B, Sirito M, Sarkar P, Krahe R, Timchenko NA, Timchenko LT (2009) Expression of RNA CCUG repeats dysregulates translation and degradation of proteins in myotonic dystrophy 2 patients. Am J Pathol 175(2):748–762.  https://doi.org/10.2353/ajpath.2009.090047 CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Chen W, Wang Y, Abe Y, Cheney L, Udd B, Li YP (2007) Haploinsuffciency for Znf9 in Znf9+/− mice is associated with multiorgan abnormalities resembling myotonic dystrophy. J Mol Biol 368(1):8–17.  https://doi.org/10.1016/j.jmb.2007.01.088 CrossRefPubMedGoogle Scholar
  97. 97.
    Margolis JM, Schoser BG, Moseley ML, Day JW, Ranum LP (2006) DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression. Hum Mol Genet 15(11):1808–1815.  https://doi.org/10.1093/hmg/ddl103 CrossRefPubMedGoogle Scholar
  98. 98.
    Raheem O, Olufemi SE, Bachinski LL, Vihola A, Sirito M, Holmlund-Hampf J, Haapasalo H, Li YP, Udd B, Krahe R (2010) Mutant (CCTG)n expansion causes abnormal expression of zinc finger protein 9 (ZNF9) in myotonic dystrophy type 2. Am J Pathol 177(6):3025–3036.  https://doi.org/10.2353/ajpath.2010.100179 CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Zamecnik PC, Stephenson ML (1978) Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A 75(1):280–284CrossRefGoogle Scholar
  100. 100.
    Kole R, Krainer AR, Altman S (2012) RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov 11(2):125–140.  https://doi.org/10.1038/nrd3625 CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Wheeler TM, Leger AJ, Pandey SK, MacLeod AR, Nakamori M, Cheng SH, Wentworth BM, Bennett CF, Thornton CA (2012) Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature 488(7409):111–115.  https://doi.org/10.1038/nature11362 CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Seth PP, Siwkowski A, Allerson CR, Vasquez G, Lee S, Prakash TP, Wancewicz EV, Witchell D, Swayze EE (2009) Short antisense oligonucleotides with novel 2′-4′ conformationaly restricted nucleoside analogues show improved potency without increased toxicity in animals. J Med Chem 52(1):10–13.  https://doi.org/10.1021/jm801294h CrossRefPubMedGoogle Scholar
  103. 103.
    Burel SA, Han SR, Lee HS, Norris DA, Lee BS, Machemer T, Park SY, Zhou T, He G, Kim Y, MacLeod AR, Monia BP, Lio S, Kim TW, Henry SP (2013) Preclinical evaluation of the toxicological effects of a novel constrained ethyl modified antisense compound targeting signal transducer and activator of transcription 3 in mice and cynomolgus monkeys. Nucleic Acid Ther 23(3):213–227.  https://doi.org/10.1089/nat.2013.0422 CrossRefPubMedGoogle Scholar
  104. 104.
    Pandey SK, Wheeler TM, Justice SL, Kim A, Younis HS, Gattis D, Jauvin D, Puymirat J, Swayze EE, Freier SM, Bennett CF, Thornton CA, MacLeod AR (2015) 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 355(2):329–340.  https://doi.org/10.1124/jpet.115.226969 CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Wojtkowiak-Szlachcic A, Taylor K, Stepniak-Konieczna E, Sznajder LJ, Mykowska A, Sroka J, Thornton CA, Sobczak K (2015) Short antisense-locked nucleic acids (all-LNAs) correct alternative splicing abnormalities in myotonic dystrophy. Nucleic Acids Res 43(6):3318–3331.  https://doi.org/10.1093/nar/gkv163 CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Weiss B, Davidkova G, Zhou LW (1999) Antisense RNA gene therapy for studying and modulating biological processes. Cell Mol Life Sci 55(3):334–358.  https://doi.org/10.1007/s000180050296 CrossRefPubMedGoogle Scholar
  107. 107.
    Furling D, Doucet G, Langlois MA, Timchenko L, Belanger E, Cossette L, Puymirat J (2003) Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions. Gene Ther 10(9):795–802.  https://doi.org/10.1038/sj.gt.3301955 CrossRefPubMedGoogle Scholar
  108. 108.
    Francois V, Klein AF, Beley C, Jollet A, Lemercier C, Garcia L, Furling D (2011) Selective silencing of mutated mRNAs in DM1 by using modified hU7-snRNAs. Nat Struct Mol Biol 18(1):85–87.  https://doi.org/10.1038/nsmb.1958 CrossRefPubMedGoogle Scholar
  109. 109.
    Langlois MA, Boniface C, Wang G, Alluin J, Salvaterra PM, Puymirat J, Rossi JJ, Lee NS (2005) Cytoplasmic and nuclear retained DMPK mRNAs are targets for RNA interference in myotonic dystrophy cells. J Biol Chem 280(17):16949–16954.  https://doi.org/10.1074/jbc.M501591200 CrossRefPubMedGoogle Scholar
  110. 110.
    Sobczak K, Wheeler TM, Wang W, Thornton CA (2013) RNA interference targeting CUG repeats in a mouse model of myotonic dystrophy. Mol Ther 21(2):380–387.  https://doi.org/10.1038/mt.2012.222 CrossRefPubMedGoogle Scholar
  111. 111.
    Bisset DR, Stepniak-Konieczna EA, Zavaljevski M, Wei J, Carter GT, Weiss MD, Chamberlain JR (2015) Therapeutic impact of systemic AAV-mediated RNA interference in a mouse model of myotonic dystrophy. Hum Mol Genet 24(17):4971–4983.  https://doi.org/10.1093/hmg/ddv219 CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Sioud M (2004) Ribozyme- and siRNA-mediated mRNA degradation: a general introduction. Methods Mol Biol 252:1–8.  https://doi.org/10.1385/1-59259-746-7:001 CrossRefPubMedGoogle Scholar
  113. 113.
    Fedor MJ, Williamson JR (2005) The catalytic diversity of RNAs. Nat Rev Mol Cell Biol 6(5):399–412.  https://doi.org/10.1038/nrm1647 CrossRefPubMedGoogle Scholar
  114. 114.
    Phylactou LA, Darrah C, Wood MJ (1998) Ribozyme-mediated trans-splicing of a trinucleotide repeat. Nat Genet 18(4):378–381.  https://doi.org/10.1038/ng0498-378 CrossRefPubMedGoogle Scholar
  115. 115.
    Langlois MA, Lee NS, Rossi JJ, Puymirat J (2003) Hammerhead ribozyme-mediated destruction of nuclear foci in myotonic dystrophy myoblasts. Mol Ther 7(5 Pt 1):670–680CrossRefGoogle Scholar
  116. 116.
    Choudhury R, Tsai YS, Dominguez D, Wang Y, Wang Z (2012) Engineering RNA endonucleases with customized sequence specificities. Nat Commun 3:1147.  https://doi.org/10.1038/ncomms2154 CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Zhang W, Wang Y, Dong S, Choudhury R, Jin Y, Wang Z (2014) Treatment of type 1 myotonic dystrophy by engineering site-specific RNA endonucleases that target (CUG)(n) repeats. Mol Ther 22(2):312–320.  https://doi.org/10.1038/mt.2013.251 CrossRefPubMedGoogle Scholar
  118. 118.
    Goyenvalle A, Davies KE (2011) Challenges to oligonucleotides-based therapeutics for Duchenne muscular dystrophy. Skelet Muscle 1(1):8.  https://doi.org/10.1186/2044-5040-1-8 CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Arechavala-Gomeza V, Anthony K, Morgan J, Muntoni F (2012) Antisense oligonucleotide-mediated exon skipping for Duchenne muscular dystrophy: progress and challenges. Curr Gene Ther 12(3):152–160CrossRefGoogle Scholar
  120. 120.
    Wheeler TM, Lueck JD, Swanson MS, Dirksen RT, Thornton CA (2007) Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy. J Clin Invest 117(12):3952–3957.  https://doi.org/10.1172/JCI33355 CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Wheeler TM, Sobczak K, Lueck JD, Osborne RJ, Lin X, Dirksen RT, Thornton CA (2009) Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 325(5938):336–339.  https://doi.org/10.1126/science.1173110 CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Mulders SA, van den Broek WJ, Wheeler TM, Croes HJ, van Kuik-Romeijn P, de Kimpe SJ, Furling D, Platenburg GJ, Gourdon G, Thornton CA, Wieringa B, Wansink DG (2009) Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy. Proc Natl Acad Sci U S A 106(33):13915–13920.  https://doi.org/10.1073/pnas.0905780106 CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Wojtkowiak JW, Cornnell HC, Matsumoto S, Saito K, Takakusagi Y, Dutta P, Kim M, Zhang X, Leos R, Bailey KM, Martinez G, Lloyd MC, Weber C, Mitchell JB, Lynch RM, Baker AF, Gatenby RA, Rejniak KA, Hart C, Krishna MC, Gillies RJ (2015) Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302. Cancer Metab 3(1):2.  https://doi.org/10.1186/s40170-014-0026-z CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Leger AJ, Mosquea LM, Clayton NP, Wu IH, Weeden T, Nelson CA, Phillips L, Roberts E, Piepenhagen PA, Cheng SH, Wentworth BM (2013) Systemic delivery of a peptide-linked morpholino oligonucleotide neutralizes mutant RNA toxicity in a mouse model of myotonic dystrophy. Nucleic Acid Ther 23(2):109–117.  https://doi.org/10.1089/nat.2012.0404 CrossRefPubMedGoogle Scholar
  125. 125.
    El-Andaloussi S, Lee Y, Lakhal-Littleton S, Li J, Seow Y, Gardiner C, Alvarez-Erviti L, Sargent IL, Wood MJ (2012) Exosome-mediated delivery of siRNA in vitro and in vivo. Nat Protoc 7(12):2112–2126.  https://doi.org/10.1038/nprot.2012.131 CrossRefPubMedGoogle Scholar
  126. 126.
    Arambula JF, Ramisetty SR, Baranger AM, Zimmerman SC (2009) A simple ligand that selectively targets CUG trinucleotide repeats and inhibits MBNL protein binding. Proc Natl Acad Sci U S A 106(38):16068–16073.  https://doi.org/10.1073/pnas.0901824106 CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Coonrod LA, Nakamori M, Wang W, Carrell S, Hilton CL, Bodner MJ, Siboni RB, Docter AG, Haley MM, Thornton CA, Berglund JA (2013) Reducing levels of toxic RNA with small molecules. ACS Chem Biol 8(11):2528–2537.  https://doi.org/10.1021/cb400431f CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Ofori LO, Hoskins J, Nakamori M, Thornton CA, Miller BL (2012) 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 40(13):6380–6390.  https://doi.org/10.1093/nar/gks298 CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Warf MB, Nakamori M, Matthys CM, Thornton CA, Berglund JA (2009) Pentamidine reverses the splicing defects associated with myotonic dystrophy. Proc Natl Acad Sci U S A 106(44):18551–18556.  https://doi.org/10.1073/pnas.0903234106 CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Childs-Disney JL, Hoskins J, Rzuczek SG, Thornton CA, Disney MD (2012) Rationally designed small molecules targeting the RNA that causes myotonic dystrophy type 1 are potently bioactive. ACS Chem Biol 7(5):856–862.  https://doi.org/10.1021/cb200408a CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Childs-Disney JL, Parkesh R, Nakamori M, Thornton CA, Disney MD (2012) Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy type 1. ACS Chem Biol 7(12):1984–1993.  https://doi.org/10.1021/cb3001606 CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Childs-Disney JL, Stepniak-Konieczna E, Tran T, Yildirim I, Park H, Chen CZ, Hoskins J, Southall N, Marugan JJ, Patnaik S, Zheng W, Austin CP, Schatz GC, Sobczak K, Thornton CA, Disney MD (2013) Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules. Nat Commun 4:2044.  https://doi.org/10.1038/ncomms3044 CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Gareiss PC, Sobczak K, McNaughton BR, Palde PB, Thornton CA, Miller BL (2008) Dynamic combinatorial selection of molecules capable of inhibiting the (CUG) repeat RNA-MBNL1 interaction in vitro: discovery of lead compounds targeting myotonic dystrophy (DM1). J Am Chem Soc 130(48):16254–16261.  https://doi.org/10.1021/ja804398y CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Pushechnikov A, Lee MM, Childs-Disney JL, Sobczak K, French JM, Thornton CA, Disney MD (2009) Rational design of ligands targeting triplet repeating transcripts that cause RNA dominant disease: application to myotonic muscular dystrophy type 1 and spinocerebellar ataxia type 3. J Am Chem Soc 131(28):9767–9779.  https://doi.org/10.1021/ja9020149 CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Garcia-Lopez A, Llamusi B, Orzaez M, Perez-Paya E, Artero RD (2011) 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 108(29):11866–11871.  https://doi.org/10.1073/pnas.1018213108 CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Chamberlain CM, Ranum LP (2012) Mouse model of muscleblind-like 1 overexpression: skeletal muscle effects and therapeutic promise. Hum Mol Genet 21(21):4645–4654.  https://doi.org/10.1093/hmg/dds306 CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Kanadia RN, Shin J, Yuan Y, Beattie SG, Wheeler TM, Thornton CA, Swanson MS (2006) 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 103(31):11748–11753.  https://doi.org/10.1073/pnas.0604970103 CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Cai L, Koppanati BM, Bertoni C, Clemens PR (2014) In utero delivery of oligodeoxynucleotides for gene correction. Methods Mol Biol 1114:399–411.  https://doi.org/10.1007/978-1-62703-761-7_26 CrossRefPubMedGoogle Scholar
  139. 139.
    Dastidar S, Ardui S, Singh K, Majumdar D, Nair N, Fu Y, Reyon D, Samara E, Gerli MFM, Klein AF, De Schrijver W, Tipanee J, Seneca S, Tulalamba W, Wang H, Chai YC, In’t Veld P, Furling D, Tedesco FS, Vermeesch JR, Joung JK, Chuah MK, VandenDriessche T (2018) Efficient CRISPR/Cas9-mediated editing of trinucleotide repeat expansion in myotonic dystrophy patient-derived iPS and myogenic cells. Nucleic Acids Res 46(16):8275–8298Google Scholar
  140. 140.
    Kleinstiver BP, Pattanayak V, Prew MS, Tsai SQ, Nguyen NT, Zheng Z, Joung JK (2016) High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. Nature 529(7587):490–495.  https://doi.org/10.1038/nature16526 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Gene Therapy & Regenerative Medicine, Faculty of Medicine & PharmacyFree University of Brussels (VUB)BrusselsBelgium
  2. 2.Center for Molecular & Vascular Biology, Department of Cardiovascular SciencesUniversity of LeuvenLeuvenBelgium

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