Top

Published in:

14-07-2023 | Myotonic Dystrophy

Update on Therapy for Myotonic Dystrophy Type 1

Authors: Vukan Ivanovic, MD, Giovani Meola, MD, PhD, neurologist, proffesor, Zoran Vukojevic, MD, PhD, neurologist, associated proffesor, Stojan Peric, MD, PhD, neurologist

Published in: Current Treatment Options in Neurology | Issue 8/2023

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.

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.

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.CrossRefPubMed

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.

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.CrossRefPubMed

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

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.

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.

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

11.

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

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.PubMed

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.PubMedPubMedCentral

15.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRef

37.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

73.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

110.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

Title: Update on Therapy for Myotonic Dystrophy Type 1
Authors: Vukan Ivanovic, MD
Giovani Meola, MD, PhD, neurologist, proffesor
Zoran Vukojevic, MD, PhD, neurologist, associated proffesor
Stojan Peric, MD, PhD, neurologist
Publication date: 14-07-2023
Publisher: Springer US
Keywords: Myotonic Dystrophy
Myotonic Dystrophy
Myotonia
Myotonia
Published in: Current Treatment Options in Neurology / Issue 8/2023
Print ISSN: 1092-8480
Electronic ISSN: 1534-3138
DOI: https://doi.org/10.1007/s11940-023-00760-9

2024 ASCO Annual Meeting

Springer Medicine

Update on Therapy for Myotonic Dystrophy Type 1

Abstract

Purpose of review

Recent findings

Summary

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Purpose of review

Recent findings

Summary

Please log in to get access to this content