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Update on Therapy for Myotonic Dystrophy Type 1

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Abstract

Purpose of review

This review aimed to summarize the clinical characteristics of myotonic dystrophy type 1 and to provide a comprehensive review of the current management options for DM1 patients.

Recent findings

Tremendous advances in understanding the molecular pathophysiology of the disease have led to the first successful preclinical or even clinical studies of disease-modifying therapies. Repurposed small molecules, such are metformin and tideglusib, are probably closest to receiving market authorization, although they showed limited clinical efficiency in treated patients. In the last decade, different synthetic therapeutic oligonucleotides (STO) able to degrade toxic DMPK mRNA were successfully tested in DM1 preclinical studies. Following the failure of the first clinical trial of an STO in DM1 due to poor peripheral drug biodistribution, clinical studies of two other STOs, namely, AOC 1001 and DYNE-101, have been initiated in the past 2 years. Preliminary results revealed successful drug delivery to the targeted tissues with significant clinical efficacy and a satisfactory safety profile. Furthermore, promising preclinical results have been disclosed for CRISPR-based genetic modifying therapy.

Summary

As there is currently no approved disease-specific therapy, a multidisciplinary approach and symptomatic therapy following recently proposed consensus-based care recommendations remain the pillars of good clinical practice managing DM1 patients. Nevertheless, significant breakthroughs in the field of oligonucleotide-based and gene therapy herald the exciting times of great potential for introducing the first causal therapy targeting the genetic cause of DM1.

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References and Recommended Reading

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

  1. Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani 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 Feb 21;68(4):799–808. https://doi.org/10.1016/0092-8674(92)90154-5.

  2. Aslanidis C, Jansen G, Amemiya C, Shutler G, Mahadevan M, Tsilfidis C, et al. Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature. 1992;355(6360):548–51. https://doi.org/10.1038/355548a0.

    Article  CAS  PubMed  Google Scholar 

  3. Bird TD. Myotonic Dystrophy Type 1. 1999 Sep 17 [updated 2021 Mar 25]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023. PMID: 20301344.

  4. Liao Q, Zhang Y, He J, Huang K. Global prevalence of myotonic dystrophy: an updated systematic review and meta-analysis. Neuroepidemiology. 2022;56:163–73. https://doi.org/10.1159/000524734.

    Article  PubMed  Google Scholar 

  5. Udd B, Krahe R. The myotonic dystrophies: molecular, clinical, and therapeutic challenges. Lancet Neurol. 2012;11(10):891–905.

    Article  CAS  PubMed  Google Scholar 

  6. Johnson NE, Butterfield RJ, Mayne K, Newcomb T, Imburgia C, Dunn D, Duval B, Feldkamp ML, Weiss RB. Population-based prevalence of myotonic dystrophy type 1 using genetic analysis of statewide blood screening program. Neurology. 2021 Feb 16;96(7):e1045–e1053. https://doi.org/10.1212/WNL.0000000000011425. Epub 2021 Jan 20. PMID: 33472919; PMCID: PMC8055332.

  7. Suominen T, Bachinski LL, Auvinen S, Hackman P, Baggerly KA, Angelini C et al. Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland. Eur J Hum Genet. 2011 Jul;19(7):776–82. https://doi.org/10.1038/ejhg.2011.23. Epub 2011 Mar 2. PMID: 21364698; PMCID: PMC3137497.

  8. Pagola-Lorz I, Vicente E, Ibáñez B, Torné L, Elizalde-Beiras I, Garcia-Solaesa V, García F, Delfrade J, Jericó I. Epidemiological study and genetic characterization of inherited muscle diseases in a northern Spanish region. Orphanet J Rare Dis. 2019;14(1):276. https://doi.org/10.1186/s13023-019-1227-x.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Mathieu J, Prévost C. Epidemiological surveillance of myotonic dystrophy type 1: a 25-year population-based study. Neuromuscul Disord. 2012;22(11):974–9. https://doi.org/10.1016/j.nmd.2012.05.017. Epub 2012 Aug 1 PMID: 22858159.

    Article  PubMed  Google Scholar 

  10. Yamagata H, Nakagawa M, Johnson K, Miki T. Further evidence for a major ancient mutation underlying myotonic dystrophy from linkage disequilibrium studies in the Japanese population. J Hum Genet. 1998;43(4):246–9.

    Article  CAS  PubMed  Google Scholar 

  11. Ashizawa T, Epstein HF. Ethnic distribution of myotonic dystrophy gene. Lancet. 1991;338(8767):642–3.

    Article  CAS  PubMed  Google Scholar 

  12. Nakagawa M, Nakahara K, Yoshidome H, Suehara M, Higuchi I, Fujiyama J, Nakamura A, Kubota R, Takenaga S, Arahata K, et al. Epidemiology of progressive muscular dystrophy in Okinawa, Japan. Classification with molecular biological techniques Neuroepidemiology. 1991;10(4):185–91.

    CAS  PubMed  Google Scholar 

  13. Hsiao KM, Chen SS, Li SY, Chiang SY, Lin HM, Pan H, Huang CC, Kuo HC, Jou SB, Su CC, Ro LS, Liu CS, Lo MC, Chen CM, Lin CC. Epidemiological and genetic studies of myotonic dystrophy type 1 in Taiwan. Neuroepidemiology. 2003;22(5):283–9. https://doi.org/10.1159/000071191. PMID: 12902623.

  14. Krahe R, Eckhart M, Ogunniyi AO, Osuntokun BO, Siciliano MJ, Ashizawa T. De novo myotonic dystrophy mutation in a Nigerian kindred. Am J Hum Genet. 1995;56:1067–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Worku DK. Concurrence of myotonic dystrophy and epilepsy: a case report. J Med Case Rep. 2015;8:427.

    Article  Google Scholar 

  16. 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. Epub 2014 May 29 PMID: 24882752.

    Article  CAS  PubMed  Google Scholar 

  17. Rakocević-Stojanović V, Savić D, Pavlović S, Lavrnić D, Stević Z, Basta I, Romac S, Apostolski S. Intergenerational changes of CTG repeat depending on the sex of the transmitting parent in myotonic dystrophy type 1. Eur J Neurol. 2005;12(3):236–7.

    Article  PubMed  Google Scholar 

  18. Higham CF, Morales F, Cobbold CA, Haydon DT, Monckton DG. High levels of somatic DNA diversity at the myotonic dystrophy type 1 locus are driven by ultra-frequent expansion and contraction mutations. Hum Mol Genet. 2012;21(11):2450–63. https://doi.org/10.1093/hmg/dds059. Epub 2012 Feb 24 PMID: 22367968.

    Article  CAS  PubMed  Google Scholar 

  19. Cumming SA, Jimenez-Moreno C, Okkersen K, Wenninger S, Daidj F, Hogarth F, Littleford R, Gorman G, Bassez G, Schoser B, Lochmüller H, van Engelen BGM, Monckton DG; OPTIMISTIC Consortium. Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort. Neurology. 2019;93(10):e995–e1009. https://doi.org/10.1212/WNL.0000000000008056. Epub 2019 Aug 8. Erratum in: Neurology. 2020 Mar 10;94(10):459. PMID: 31395669; PMCID: PMC6745735.

  20. Klein AF, Gasnier E, Furling D. Gain of RNA function in pathological cases: focus on myotonic dystrophy. Biochimie. 2011;93(11):2006–12.

    Article  CAS  PubMed  Google Scholar 

  21. Jiang H, Mankodi A, Swanson MS, Moxley RT, Thornton CA. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol Genet. 2004;13(24):3079–88.

    Article  CAS  PubMed  Google Scholar 

  22. Mankodi A, Teng-Umnuay P, Krym M, Henderson D, Swanson M, Thornton CA. Ribonuclear inclusions in skeletal muscle in myotonic dystrophy types 1 and 2. Ann Neurol. 2003;54(6):760–8.

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. Chau A, Kalsotra A. Developmental insights into the pathology of and therapeutic strategies for DM1: back to the basics. Dev Dyn. 2015:377–390. https://doi.org/10.1002/dvdy.24240.

  25. Kalsotra A, Xiao X, Ward AJ, Castle JC, Johnson JM, Burge CB, et al. A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc Natl Acad Sci USA. 2008;105:20333–8. https://doi.org/10.1073/pnas.0809045105.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lin X, Miller JW, Mankodi A, Kanadia RN, Yuan Y, Moxley RT, et al. Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum Mol Genet. 2006;15:2087–97. https://doi.org/10.1093/hmg/ddl132.

    Article  CAS  PubMed  Google Scholar 

  27. • López-Martínez A, Soblechero-Martín P, de-la-Puente-Ovejero L, Nogales-Gadea G, Arechavala-Gomeza V. An overview of alternative splicing defects implicated in myotonic dystrophy type I. Genes (Basel). 2020 Sep 22;11(9):1109. https://doi.org/10.3390/genes11091109. Overview of the DM1 pathophysiology.

  28. Furling D, Lemieux D, Taneja K, Puymirat J. Decreased levels of myotonic dystrophy protein kinase (DMPK) and delayed differentiation in human myotonic dystrophy myoblasts. Neuromuscul Disord. 2001;11(8):728–35.

    Article  CAS  PubMed  Google Scholar 

  29. Yin Q, Wang H, Li N, Ding Y, Xie Z, Jin L, et al. Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1. Cell Res. 2020;30(2):133–45. https://doi.org/10.1038/s41422-019-0264-2.

    Article  CAS  PubMed  Google Scholar 

  30. Reddy S, Smith DB, Rich MM, Leferovich JM, Reilly P, Davis BM, et al. Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy. Nat Genet. 1996;13:325–35.

    Article  CAS  PubMed  Google Scholar 

  31. Berul CI, Maguire CT, Gehrmann J, Reddy S. Progressive atrioventricular conduction block in a mouse myotonic dystrophy model. J Interv Card Electrophysiol. 2000;4:351–8.

    Article  CAS  PubMed  Google Scholar 

  32. Sarkar PS, et al. Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts. Nat Genet. 2000;25:110–4. https://doi.org/10.1038/75500.

    Article  CAS  PubMed  Google Scholar 

  33. Cleary JD, Pattamatta A, Ranum LPW. Repeat-associated non-ATG (RAN) translation. J Biol Chem. 2018;293(42):16127–41. https://doi.org/10.1074/jbc.R118.003237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Banez-Coronel M, Ranum LPW. Repeat-associated non-AUG (RAN) translation: insights from pathology. Lab Invest. 2019;99(7):929–42. https://doi.org/10.1038/s41374-019-0241-x.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Koehorst E, Núñez-Manchón J, Ballester-López A, Almendrote M, Lucente G, Arbex A, et al. Characterization of RAN translation and antisense transcription in primary cell cultures of patients with myotonic dystrophy type 1. J Clin Med. 2021;10(23):5520. https://doi.org/10.3390/jcm10235520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wenninger S, Montagnese F, Schoser B. Core Clinical phenotypes in myotonic dystrophies. Front Neurol. 2018;2(9):303. https://doi.org/10.3389/fneur.2018.00303.

    Article  Google Scholar 

  37. Johnson NE, Heatwole CR. Myotonic dystrophy: from bench to bedside. Semin Neurol. 2012;32(3):246–54.

    Article  PubMed  Google Scholar 

  38. Kroksmark AK, Stridh ML, Ekström AB. Long-term follow-up of motor function and muscle strength in the congenital and childhood forms of myotonic dystrophy type 1. Neuromuscul Disord. 2017;27:826–35.

    Article  PubMed  Google Scholar 

  39. Rakocevic-Stojanovic V, Peric S, Basta I, Dobricic V, Ralic V, Kacar A, … Novakovic I. Variability of multisystemic features in myotonic dystrophy type 1 – lessons from Serbian registry. Neurol Res. 2015;37(11):939–44. https://doi.org/10.1179/1743132815y.000000006.

  40. Ikeda KS, Iwabe-Marchese C, França MC Jr, Nucci A, Carvalho KM. Myotonic dystrophy type 1: frequency of ophthalmologic findings. Arq Neuropsiquiatr. 2016;74(3):183–8. https://doi.org/10.1590/0004-282x20150218.

    Article  PubMed  Google Scholar 

  41. Kersten HM, Roxburgh RH, Child N, Polkinghorne PJ, Frampton C, Danesh-Meyer HV. Epiretinal membrane: a treatable cause of visual disability in myotonic dystrophy type 1. J Neurol. 2014;261(1):37–44. https://doi.org/10.1007/s00415-013-7141-6.

    Article  PubMed  Google Scholar 

  42. Harper PS. The eye in myotonic dystrophy. In: Harper PS editor, Myotonic dystrophy. London: WB. Saunders; 2001. Chapter 8, p. 199–221.

  43. Rakocevic Stojanovic V, Peric S, Paunic T, Pavlovic S, Cvitan E, Basta I, et al. Cardiologic predictors of sudden death in patients with myotonic dystrophy type 1. J Clin Neurosci. 2013;20(7):1002–6.

    Article  PubMed  Google Scholar 

  44. Groh WJ, Groh MR, Saha C, Kincaid JC, Simmons Z, Ciafaloni E, et al. Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med. 2008;358(25):2688–97. https://doi.org/10.1056/NEJMoa062800.

    Article  CAS  PubMed  Google Scholar 

  45. Petri H, Vissing J, Witting N, Bundgaard H, Køber L. Cardiac manifestations of myotonic dystrophy type 1. Int J Cardiol. 2012;160(2):82–8. https://doi.org/10.1016/j.ijcard.2011.08.037.

    Article  PubMed  Google Scholar 

  46. Wahbi K, Meune C, Porcher R, Bécane HM, Lazarus A, Laforêt P, Stojkovic T, Béhin A, Radvanyi-Hoffmann H, Eymard B, Duboc D. Electrophysiological study with prophylactic pacing and survival in adults with myotonic dystrophy and conduction system disease. JAMA. 2012;307(12):1292–301. https://doi.org/10.1001/jama.2012.346.

    Article  CAS  PubMed  Google Scholar 

  47. Hawkins AM, Hawkins CL, Abdul Razak K, Khoo TK, Tran K, Jackson RV. Respiratory dysfunction in myotonic dystrophy type 1: a systematic review. Neuromuscul Disord. 2019;29(3):198–212. https://doi.org/10.1016/j.nmd.2018.12.002. Epub 2018 Dec 9 PMID: 30765255.

    Article  CAS  PubMed  Google Scholar 

  48. Matsumura T, Iwahashi H, Funahashi T, Takahashi MP, Saito T, Yasui K, Saito T, Iyama A, Toyooka K, Fujimura H, Shinno S. A cross-sectional study for glucose intolerance of myotonic dystrophy. J Neurol Sci. 2009;276:60–5.

    Article  CAS  PubMed  Google Scholar 

  49. Vujnic M, Peric S, Popovic S, Raseta N, Ralic V, Dobricic V, et al. Metabolic syndrome in patients with myotonic dystrophy type 1. Muscle Nerve. 2015;52(2):273–7.

    Article  CAS  PubMed  Google Scholar 

  50. Passeri E, Bugiardini E, Sansone VA, Valaperta R, Costa E, Ambrosi B, Meola G, Corbetta S. Vitamin D, parathyroid hormone and muscle impairment in myotonic dystrophies. J Neurol Sci. 2013;331:132–5.

    Article  CAS  PubMed  Google Scholar 

  51. Dahlqvist JR, Ørngreen MC, Witting N, Vissing J. Endocrine function over time in patients with myotonic dystrophy type 1. Eur J Neurol. 2015;22(1):116–22. https://doi.org/10.1111/ene.12542.

    Article  CAS  PubMed  Google Scholar 

  52. Peric S, Bjelica B, Bozovic I, Pesovic J, Paunic T, Banovic M, et al. Fatigue in myotonic dystrophy type 1: a seven-year prospective study. Acta Myol. 2019;38(4):239–44.

    PubMed  PubMed Central  Google Scholar 

  53. Romigi A, Albanese M, Liguori C, Placidi F, Marciani MG, Massa R. Sleep-wake cycle and daytime sleepiness in the myotonic dystrophies. J Neurodegener Dis. 2013;2013:692026. https://doi.org/10.1155/2013/692026.

  54. Peric S, Sreckov M, Basta I, Lavrnic D, Vujnic M, Marjanovic I, et al. Dependent and paranoid personality patterns in myotonic dystrophy type 1. Acta Neurol Scand. 2014;129(4):219–25. https://doi.org/10.1111/ane.12173.

    Article  CAS  PubMed  Google Scholar 

  55. Minier L, Lignier B, Bouvet C, Gallais B, Camart N. A review of psychopathology features, personality, and coping in myotonic dystrophy type 1. J Neuromuscul Dis. 2018;5(3):279–94. https://doi.org/10.3233/JND-180310.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Caso F, Agosta F, Peric S, Rakočević-Stojanović V, Copetti M, Kostic VS, Filippi M. Cognitive impairment in myotonic dystrophy type 1 is associated with white matter damage. PLoS One. 2014 Aug 12;9(8):e104697. https://doi.org/10.1371/journal.pone.0104697.

  57. Okkersen K, Monckton DG, Le N, Tuladhar AM, Raaphorst J, van Engelen BGM. Brain imaging in myotonic dystrophy type 1: a systematic review. Neurology. 2017;89(9):960–9. https://doi.org/10.1212/WNL.0000000000004300.

    Article  PubMed  Google Scholar 

  58. Fisette-Paulhus I, Gagnon C, Girard-Côté L, Morin M. Genitourinary and lower gastrointestinal conditions in patients with myotonic dystrophy type 1: a systematic review of evidence and implications for clinical practice. Neuromuscul Disord. 2022;32(5):361–76. https://doi.org/10.1016/j.nmd.2022.01.008.

    Article  PubMed  Google Scholar 

  59. Kong HE, Pollack BP. Cutaneous findings in myotonic dystrophy. JAAD Int. 2022;22(7):7–12. https://doi.org/10.1016/j.jdin.2021.09.008.

    Article  Google Scholar 

  60. Gadalla SM, Lund M, Pfeiffer RM, Gørtz S, Mueller CM, Moxley RT 3rd, Kristinsson SY, Björkholm M, Shebl FM, Hilbert JE, Landgren O, Wohlfahrt J, Melbye M, Greene MH. Cancer risk among patients with myotonic muscular dystrophy. JAMA. 2011;306(22):2480–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hilbert JE, Ashizawa T, Day JW, Luebbe EA, Martens WB, McDermott MP, Tawil R, Thornton CA, Moxley RT 3rd. Diagnostic odyssey of patients with myotonic dystrophy. J Neurol. 2013;260(10):2497–504. https://doi.org/10.1007/s00415-013-6993-0.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Addis M, Serrenti M, Meloni C, Cau M, Melis MA. Triplet-primed PCR is more sensitive than southern blotting-long PCR for the diagnosis of myotonic dystrophy type1. Genet Test Mol Biomarkers. 2012;16(12):1428–31. https://doi.org/10.1089/gtmb.2012.0218.

    Article  CAS  PubMed  Google Scholar 

  63. Peric S, Stojanovic VR, Basta I, Peric M, Milicev M, Pavlovic S, et al. Influence of multisystemic affection on health-related quality of life in patients with myotonic dystrophy type 1. Clin Neurol Neurosurg. 2013;115(3):270–5.

    Article  CAS  PubMed  Google Scholar 

  64. Mathieu J, Allard P, Potvin L, Prévost C, Bégin P. A 10-year study of mortality in a cohort of patients with myotonic dystrophy. Neurology. 1999 12;52(8):1658–62. https://doi.org/10.1212/wnl.52.8.1658. PMID: 10331695

  65. Joosten IBT, Horlings CGC, Vosse BAH, Wagner A, Bovenkerk DSH, Evertz R, Vernooy K, van Engelen BGM, Faber CG. Myotonic dystrophy type 1: a comparison between the adult- and late-onset subtype. Muscle Nerve. 2023;67(2):130–7. https://doi.org/10.1002/mus.27766.

    Article  CAS  PubMed  Google Scholar 

  66. Ricker K, Grimm T, Koch MC, Schneider C, Kress W, Reimers CD, Schulte-Mattler W, Mueller-Myhsok B, Toyka KV, Mueller CR. Linkage of proximal myotonic myopathy to chromosome 3q. Neurology. 1999;52:170–1.

    Article  CAS  PubMed  Google Scholar 

  67. Fujino H, Saito T, Takahashi MP, Takada H, Nakayama T, Imura O, Matsumura T. Quality of life and subjective symptom impact in Japanese patients with myotonic dystrophy type 1. BMC Neurol. 2022;22(1):55. https://doi.org/10.1186/s12883-022-02581-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Logigian EL, Martens WB, Moxley RT 4th, McDermott MP, Dilek N, Wiegner AW, et al. Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1. Neurology. 2010;74(18):1441–8. https://doi.org/10.1212/WNL.0b013e3181dc1a3a.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. D’Mello S, Shum L. A review of the use of mexiletine in patients with myotonic dystrophy and non-dystrophic myotonia. Eur J Hosp Pharm. 2016;23(6):359–63. https://doi.org/10.1136/ejhpharm-2015-000839.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Heatwole C, Luebbe E, Rosero S, Eichinger K, Martens W, Hilbert J, et al. Mexiletine in myotonic dystrophy type 1: a randomized, double-blind, placebo-controlled trial. Neurology. 2021;96(2):e228–40. https://doi.org/10.1212/WNL.0000000000011002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Study to investigate the efficacy and safety of mexiletine in patients with myotonic dystrophy type 1 and type 2 (MIND). https://clinicaltrials.gov/ct2/show/NCT04700046. [Accessed 5 May 2023].

  72. • Ashizawa T, Gagnon C, Groh WJ, Gutmann L, Johnson NE, Meola G, et al. Consensus-based care recommendations for adults with myotonic dystrophy type 1. Neurol Clin Pract. 2018;8(6):507–20. https://doi.org/10.1212/CPJ.0000000000000531. MDF consensus-based experts’ recommendations for the management of DM1 patients.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Penisson-Besnier I, Devillers M, Porcher R, et al. Dehydroepiandrosterone for myotonic dystrophy type 1. Neurology. 2008;71:407–12.

    Article  CAS  PubMed  Google Scholar 

  74. Heatwole CR, Eichinger KJ, Friedman DI, et al. Open-label trial of recombinant human insulin-like growth factor 1/recombinant human insulin-like growth factor binding protein 3 in myotonic dystrophy type 1. Arch Neurol. 2011;68:37–44.

    Article  PubMed  Google Scholar 

  75. Walter MC, Reilich P, Lochmuller H, et al. Creatine monohydrate in myotonic dystrophy: a double-blind, placebo-controlled clinical study. J Neurol. 2002;249:1717–22.

    Article  CAS  PubMed  Google Scholar 

  76. Tarnopolsky M, Mahoney D, Thompson T, et al. Creatine monohydrate supplementation does not increase muscle strength, lean body mass, or muscle phosphocreatine in patients with myotonic dystrophy type 1. Muscle Nerve. 2004;29:51–8.

    Article  CAS  PubMed  Google Scholar 

  77. Roussel MP, Morin M, Gagnon C, Duchesne E. What is known about the effects of exercise or training to reduce skeletal muscle impairments of patients with myotonic dystrophy type 1? A scoping review. BMC Musculoskelet Disord. 2019;20(1):101. https://doi.org/10.1186/s12891-019-2458-7.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Duda J, Venkatesh Y, Groh W. Causes and predictors of mortality in a large U.S. myotonic dystrophy type 1 adult cohort. Neurology. 2016; 86(16 Supplement) P5.077.

  79. de Die-Smulders CE, Höweler CJ, Thijs C, Mirandolle JF, Anten HB, Smeets HJ, Chandler KE, Geraedts JP. Age and causes of death in adult-onset myotonic dystrophy. Brain. 1998;121:1557–63. https://doi.org/10.1093/brain/121.8.1557.

    Article  PubMed  Google Scholar 

  80. • McNally EM, Mann DL, Pinto Y, Bhakta D, Tomaselli G, Nazarian S et al. Clinical care recommendations for cardiologists treating adults with myotonic dystrophy. J Am Heart Assoc. 2020 Feb 18;9(4):e014006. https://doi.org/10.1161/JAHA.119.014006. Expert consensus recommendations on the cardiac management in DM1 patients.

  81. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA, Freedman RA, Gettes LS et al. American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Heart Rhythm Society. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2013 Jan 22;61(3):e6–75. https://doi.org/10.1016/j.jacc.2012.11.007.

  82. McNally EM, Sparano D. Mechanisms and management of the heart in myotonic dystrophy. Heart. 2011;97(13):1094–100.

    Article  PubMed  Google Scholar 

  83. • Boentert M, Cao M, Mass D, De Mattia E, Falcier E, Goncalves M, et al. Consensus-based care recommendations for pulmonologists treating adults with myotonic dystrophy type 1. Respiration. 2020;99(4):360–8. https://doi.org/10.1159/000505634. Expert consensus recommendations on the respiratory management in DM1 patients.

    Article  PubMed  Google Scholar 

  84. American Diabetes Association Professional Practice Committee. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2022. Diabetes Care. 2022 Jan 1;45(Suppl 1):S17-S38. https://doi.org/10.2337/dc22-S002.

  85. Kouki T, Takasu N, Nakachi A, Tamanaha T, Komiya I, Tawata M. Low-dose metformin improves hyperglycemia related to myotonic dystrophy. Diabet Med. 2005;22(3):346–7.

    Article  CAS  PubMed  Google Scholar 

  86. Laberge C, Gagnon S, Mathieu J. Fatigue and daytime sleepiness rating scales in myotonic dystrophy: a study of reliability. J Neurol Neurosurg Psychiatry. 2005;76:1403–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hermans MC, Merkies IS, Laberge L, Blom EW, Tennant A, Faber CG. Fatigue and daytime sleepiness scale in myotonic dystrophy type 1. Muscle Nerve. 2013;47(1):89–95. https://doi.org/10.1002/mus.23478.

    Article  PubMed  Google Scholar 

  88. Subramony SH, Wymer JP, Pinto BS, Wang ET. Sleep disorders in myotonic dystrophies. Muscle Nerve. 2020;62(3):309–20. https://doi.org/10.1002/mus.26866.

    Article  PubMed  Google Scholar 

  89. Orlikowski D, Chevret S, Quera-Salva MA, et al. Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: a multicenter, prospective, randomized, double blind, placebo-controlled, 4-week trial. Clin Ther. 2009;31:1765–73.

    Article  CAS  PubMed  Google Scholar 

  90. Puymirat J, Bouchard JP, Mathieu J. Efficacy and tolerability of a 20-mg dose of methylphenidate for the treatment of daytime sleepiness in adult patients with myotonic dystrophy type 1: a 2-center randomized, double blind, placebo-controlled, 3-week crossover trial. Clin Ther. 2012;34:1103–11.

    Article  CAS  PubMed  Google Scholar 

  91. Effect of MYODM on quality of life, fatigue and hypersomnia in patients with myotonic dystrophy type 1. https://clinicaltrials.gov/ct2/show/NCT04634682. [Accessed 10 May 2023].

  92. Okkersen K, Jimenez-Moreno C, Wenninger S, Daidj F, Glennon J, Cumming S et al. OPTIMISTIC consortium. Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial. Lancet Neurol. 2018;17(8):671–680. https://doi.org/10.1016/S1474-4422(18)30203-5.

  93. Jones K, Pitceathly RD, Rose MR, et al. Interventions for dysphagia in long-term, progressive muscle disease. Cochrane Database Syst Rev 2016;2:CD004303.

  94. Pilz W, Baijens LW, Kremer B. Oropharyngeal dysphagia in myotonic dystrophy type 1: a systematic review. Dysphagia. 2014;29:319–31.

    Article  PubMed  Google Scholar 

  95. Campbell N, Brandom B, Day JW, Moxley R 3rd. Practical suggestions for the anesthetic management of a myotonic dystrophy patient. Myotonic dystrophy foundation MDFToolkit. 2013;23:794–803.

    Google Scholar 

  96. Moulds RFW, Denborough MA: Myopathies and malignant hyperpyrexia (Correspondence) Br Med J 1994;3:520

  97. Ishizawa Y, et al. A serious complication due to gastrointestinal malfunction in a patient with myotonic dystrophy. Anesth Analg. 1986;65:1066–8.

    Article  CAS  PubMed  Google Scholar 

  98. Gupta N, N Saxena K, Kumar Panda A, Anand R, Mishra A. Myotonic dystrophy: an anaesthetic dilemma. Indian J Anaesth. 2009;53(6):688–91. PMID: 20640098; PMCID: PMC2900080.

  99. Win AK, Perattur PG, Pulido JS, Pulido CM, Lindor NM. Increased cancer risks in myotonic dystrophy. Mayo Clin Proc. 2012;87(2):130–5.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Das M, Moxley RT 3rd, Hilbert JE, Martens WB, Letren L, Greene MH, et al. Correlates of tumor development in patients with myotonic dystrophy. J Neurol. 2012;259(10):2161–6.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Gadalla SM, Lund M, Pfeiffer RM, Gortz S, Greene MH, et al. Cancer risk among patients with myotonic muscular dystrophy. Jama. 2011;306(22):2480–6.

  102. Fernández-Torrón R, García-Puga M, Emparanza JI, Maneiro M, López de Munain A, et al. Cancer risk in DM1 is sex-related and linked to miRNA-200/141 downregulation. Neurology 2016;87(12):1250–7.

  103. • Pascual-Gilabert M, Artero R, López-Castel A. The myotonic dystrophy type 1 drug development pipeline: 2022 edition. Drug Discov Today. 2023;28(3):103489. https://doi.org/10.1016/j.drudis.2023.103489. Comprehensive recent review of the DM1 drug development. More detailed focus on preclinical trials of several potential therapeutic options for DM1 patients.

  104. Huichalaf C, Sakai K, Jin B, Jones K, Wang GL, Schoser B, et al. Expansion of CUG RNA repeats causes stress and inhibition of translation in myotonic dystrophy 1 (DM1) cells. FASEB J. 2010;24(10):3706–19. https://doi.org/10.1096/fj.09-151159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Jones K, Wei C, Iakova P, Bugiardini E, Schneider-Gold C, Meola G, Woodgett J, Killian J, Timchenko NA, Timchenko LT. GSK3β mediates muscle pathology in myotonic dystrophy. J Clin Invest. 2012;122(12):4461–72. https://doi.org/10.1172/JCI64081. Epub 2012 Nov 19. PMID: 23160194; PMCID: PMC3533547.

  106. del Ser T, Steinwachs KC, Gertz HJ, Andrés MV, Gómez-Carrillo B, Medina M, et al. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis. 2013;33(1):205–15. https://doi.org/10.3233/JAD-2012-120805.

    Article  CAS  PubMed  Google Scholar 

  107. Wang M, Weng WC, Stock L, et al. Correction of glycogen synthase kinase 3beta in myotonic dystrophy 1 reduces the mutant RNA and improves postnatal survival of DMSXL mice. Mol Cell Biol. 2019;39:(e00155–19).

  108. Horrigan J, Gomes TB, Snape M, Nikolenko N, McMorn A, Evans S, et al. A phase 2 study of AMO-02 (Tideglusib) in congenital and childhood-onset myotonic dystrophy type 1 (DM1). Pediatr Neurol. 2020;112:84–93. https://doi.org/10.1016/j.pediatrneurol.2020.08.001.

    Article  PubMed  Google Scholar 

  109. • García-Puga M, Saenz-Antoñanzas A, Matheu A, de Munain AL. Targeting myotonic dystrophy type 1 with metformin. Int J Mol Sci. 2022;23:2901. https://doi.org/10.3390/ijms23052901. Review providing summarized recent findings on metformin therapy for DM1 patients, revealing that the compound is not only the first choice oral therapy for frequently present1 glucose metabolism disorders in DM1 patients, but it also rescues multiple phenotypes of the disease with the potential to modify the disease course and improve muscular dysfunction in the affected subjects.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016;23:1060–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. García-Puga M, Saenz-Antoñanzas A, Fernández-Torrón R, Munain AL, Matheu A. Myotonic dystrophy type 1 cells display impaired metabolism and mitochondrial dysfunction that are reversed by metformin. Aging (Albany NY). 2020;12(7):6260–75. https://doi.org/10.18632/aging.103022. Epub 2020 Apr 8.

    Article  PubMed  Google Scholar 

  112. Bassez G, Audureau E, Hogrel JY, Arrouasse R, Baghdoyan S, Bhugaloo H, et al. Improved mobility with metformin in patients with myotonic dystrophy type 1: a randomized controlled trial. Brain. 2018;141(10):2855–65. https://doi.org/10.1093/brain/awy231.

    Article  PubMed  Google Scholar 

  113. Evaluation of the efficacy and safety of metformin in the myotonic dystrophy type 1 (Steinert’s disease) (METFORMYO) - https://clinicaltrials.gov/ct2/show/NCT05532813. [Accessed 10 May 2023].

  114. Moumné L, Marie AC, Crouvezier N. Oligonucleotide therapeutics: from discovery and development to patentability. Pharmaceutics. 2022;14(2):260. https://doi.org/10.3390/pharmaceutics14020260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ait Benichou S, Jauvin D, De Serres-Bérard T, Pierre M, Ling KK, Bennett C et al. Antisense oligonucleotides as a potential treatment for brain deficits observed in myotonic dystrophy type 1. Gene Ther. 2022;29(12):698-709. https://doi.org/10.1038/s41434-022-00316-7.

  116. Thornton CA, Moxley RT 3rd, Eichinger K, Heatwole C, Mignon L, Arnold WD, et al. Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial. Lancet Neurol. 2023;22(3):218–28. https://doi.org/10.1016/S1474-4422(23)00001-7.

    Article  CAS  PubMed  Google Scholar 

  117. Ait Benichou S, Jauvin D, De Serres-Bérard T, Bennett F, Rigo F, Gourdon G, et al. Enhanced delivery of ligand-conjugated antisense oligonucleotides (C16-HA-ASO) targeting dystrophia myotonica protein kinase transcripts for the treatment of myotonic dystrophy type 1. Hum Gene Ther. 2022;33(15–16):810–20. https://doi.org/10.1089/hum.2022.069.

    Article  CAS  PubMed  Google Scholar 

  118. De Serres-Bérard T, Ait Benichou S, Jauvin D, Boutjdir M, Puymirat J, Chahine M. Recent progress and challenges in the development of antisense therapies for myotonic dystrophy type 1. Int J Mol Sci. 2022;23(21):13359. https://doi.org/10.3390/ijms232113359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Paterson J, Webster CI. Exploiting transferrin receptor for delivering drugs across the blood-brain barrier. Drug Discov Today Technol. 2016;20:49–52. https://doi.org/10.1016/j.ddtec.2016.07.009.

    Article  PubMed  Google Scholar 

  120. Sugo T, Terada M, Oikawa T, Miyata K, Nishimura S, Kenjo E, et al. Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles. J Control Release. 2016;10(237):1–13. https://doi.org/10.1016/j.jconrel.2016.06.036.

    Article  CAS  Google Scholar 

  121. Avidity Biosciences. Avidity announces positive AOC 1001 Phase 1/2 MARINA™ data demonstrating first-ever successful targeted delivery of RNA to muscle – revolutionary advancement for the field of RNA therapeutics. https://aviditybiosciences.investorroom.com/2022-12-14-Avidity-Announces-Positive-AOC-1001-Phase-1-2-MARINA-TM-Data-Demonstrating-First-Ever-Successful-Targeted-Delivery-of-RNA-to-Muscle-Revolutionary-Advancement-for-the-Field-of-RNA-Therapeutics. [Accessed 10 May].

  122. •• Avidity Biosciences Announces Positive Topline Data from AOC 1001 Phase 1/2 MARINA™ Trial Demonstrating Functional Improvement, Disease Modification and Favorable Safety and Tolerability Profile in People Living with Myotonic Dystrophy Type 1(https://aviditybiosciences.investorroom.com/2023-04-27-Avidity-Biosciences-Announces-Positive-Topline-Data-from-AOC-1001-Phase-1-2-MARINA-TM-Trial-Demonstrating-Functional-Improvement,-Disease-Modification-and-Favorable-Safety-and-Tolerability-Profile-in-People-Living-with-Myotonic-Dystrophy-Type-1.com. [Accessed 10 May 2023]). Topline Data for Avidity’s antisense oligonucleotide AOC 1001 demonstrating significant functional improvement and good safety profile of the tested compound. AOC 1001, the first antibody oligonucleotide conjugate tested in clinical trials could be a first oligonucleotide-based therapy reaching market authorization for DM1 patients.

  123. Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients (MARINA-OLE) https://clinicaltrials.gov/ct2/show/NCT05479981. [Accessed 10 May 2023].

  124. •• Safety, Tolerability, Pharmacodynamic, Efficacy, and Pharmacokinetic Study of DYNE-101 in Participants With Myotonic Dystrophy Type 1 (ACHIEVE) https://clinicaltrials.gov/ct2/show/NCT05481879. [Accessed 10 May 2023]. DYNE-101 is a third antisense oligonucleotide that reached clinical trial in DM1 patients. Improved peripheral biodistribution of the compound and favorable preclinical data raises optimism while waiting for the first clinical results.

  125. Dyne Therapeutics. Muscle targeting complexes and uses thereof for treating myotonic dystrophy. EP3829596A1. https://uspto.report/patent/app/20210308273 [accessed 10 May 2023].

  126. Dyne Therapeutics. The FORCE™platform achieves durable knockdown of toxic human nuclear DMPK RNA and correction of splicing in the hTfR1/DMSXL mouse model. [Accesed 10 May 2023].

  127. Entrada. A novel EEV-conjugated PMO, ENTR-701, reduces nuclear foci and corrects aberrant splicing in myotonic dystrophy type 1 preclinical models. [Accessed 10 May 2023].

  128. Astellas Pharma. Method for treating muscular dystrophy by targeting DMPK. WO2020241903A1. https://uspto.report/patent/app/20210355464. [Accessed 10 May 2023].

  129. 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 

  130. Cerro-Herreros E, Sabater-Arcis M, Fernandez-Costa JM, Moreno N, Perez-Alonso M, Llamusi B, et al. miR-23b and miR-218 silencing increase muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models. Nat Commun. 2018;9(1):2482. https://doi.org/10.1038/s41467-018-04892-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Myotonic Foundation. Arthex Biotech – meet the DM drug developers. https://www.myotonic.org/digital-academy/arthex-biotech-meet-dm-drug-developers-0. [Accessed 10 May 2023].

  132. Overby SJ, Cerro-Herreros E, González-Martínez I, Varela MA, Seoane-Miraz D, Jad Y, et al. Proof of concept of peptide-linked blockmiR-induced MBNL functional rescue in myotonic dystrophy type 1 mouse model. Mol Ther Nucleic Acids. 2022;10(27):1146–55. https://doi.org/10.1016/j.omtn.2022.02.003.

    Article  CAS  Google Scholar 

  133. LocanaBio. A pipeline to treat severe genetic diseases. https://locanabio.com/pipeline/. [Accessed 10 May 2023].

  134. Lo Scrudato M, Poulard K, Sourd C, Tomé S, Klein AF, Corre G, et al. Genome editing of expanded CTG repeats within the human DMPK gene reduces nuclear RNA foci in the muscle of DM1 mice. Mol Ther. 2019;27(8):1372–88. https://doi.org/10.1016/j.ymthe.2019.05.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Batra R, Nelles DA, Roth DM, Krach F, Nutter CA, Tadokoro T, et al. The sustained expression of Cas9 targeting toxic RNAs reverses disease phenotypes in mouse models of myotonic dystrophy type 1. Nat Biomed Eng. 2021;5(2):157–68. https://doi.org/10.1038/s41551-020-00607-7.

    Article  CAS  PubMed  Google Scholar 

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The publication fees will be paid by the Fondazione Malattie Miotoniche (FMM), Milan, Italy.

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  1. Neurology Clinic, Faculty of Medicine, University Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia

    Vukan Ivanovic MD & Stojan Peric MD, PhD, neurologist

  2. Department of Biomedical Sciences for Health, University of Milan, Casa Di Cura Igea, Milan, Italy

    Giovani Meola MD, PhD, neurologist, proffesor

  3. Clinic of Neurology, Faculty of Medicine, University Clinical Center of Republic of Srpska, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina

    Zoran Vukojevic MD, PhD, neurologist, associated proffesor

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Ivanovic, V., Meola, G., Vukojevic, Z. et al. Update on Therapy for Myotonic Dystrophy Type 1. Curr Treat Options Neurol 25, 261–279 (2023). https://doi.org/10.1007/s11940-023-00760-9

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