Therapeutics Development in Myotonic Dystrophy Type 1

Overview

Journal Muscle Nerve

Date 2011 May 25

PMID 21607985

Citations 23

Authors

Erin Pennock Foff

Mani S Mahadevan

Affiliations

Soon will be listed here.

Abstract

Myotonic dystrophy (DM1), the most common adult muscular dystrophy, is a multisystem, autosomal dominant genetic disorder caused by an expanded CTG repeat that leads to nuclear retention of a mutant RNA and subsequent RNA toxicity. Significant insights into the molecular mechanisms of RNA toxicity have led to the previously unforeseen possibility that treating DM1 is a viable prospect. In this review, we briefly present the clinical picture in DM1, and describe how the research in understanding the pathogenesis of RNA toxicity in DM1 has led to targeted approaches to therapeutic development at various steps in the pathogenesis of the disease. We discuss the promise and current limitations of each with an emphasis on RNA-based therapeutics and small molecules. We conclude with a discussion of the unmet need for clinical tools and outcome measures that are essential prerequisites to proceed in evaluating these potential therapies in clinical trials.

Citing Articles

miR-223-3p and miR-24-3p as novel serum-based biomarkers for myotonic dystrophy type 1.

Koutalianos D, Koutsoulidou A, Mytidou C, Kakouri A, Oulas A, Tomazou M Mol Ther Methods Clin Dev. 2021; 23:169-183.

PMID: 34703840 PMC: 8517008. DOI: 10.1016/j.omtm.2021.09.007.

Responsiveness of outcome measures in myotonic dystrophy type 1.

Knak K, Sheikh A, Witting N, Vissing J Ann Clin Transl Neurol. 2020; 7(8):1382-1391.

PMID: 32672404 PMC: 7448158. DOI: 10.1002/acn3.51129.

Resveratrol corrects aberrant splicing of pre-mRNA and Ca signal in myotonic dystrophy type 1 myotubes.

Santoro M, Piacentini R, Perna A, Pisano E, Severino A, Modoni A Neural Regen Res. 2020; 15(9):1757-1766.

PMID: 32209783 PMC: 7437583. DOI: 10.4103/1673-5374.276336.

miR-7 Restores Phenotypes in Myotonic Dystrophy Muscle Cells by Repressing Hyperactivated Autophagy.

Sabater-Arcis M, Bargiela A, Furling D, Artero R Mol Ther Nucleic Acids. 2019; 19:278-292.

PMID: 31855836 PMC: 6926285. DOI: 10.1016/j.omtn.2019.11.012.

Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models.

Bargiela A, Sabater-Arcis M, Espinosa-Espinosa J, Zulaica M, de Munain A, Artero R Proc Natl Acad Sci U S A. 2019; 116(50):25203-25213.

PMID: 31754023 PMC: 6911202. DOI: 10.1073/pnas.1820297116.

References

Krol J, Fiszer A, Mykowska A, Sobczak K, de Mezer M, Krzyzosiak W . Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets. Mol Cell. 2007; 25(4):575-86. DOI: 10.1016/j.molcel.2007.01.031. View

Bassez G, Lazarus A, Desguerre I, Varin J, Laforet P, Becane H . Severe cardiac arrhythmias in young patients with myotonic dystrophy type 1. Neurology. 2004; 63(10):1939-41. DOI: 10.1212/01.wnl.0000144343.91136.cf. View

Lee M, Pushechnikov A, Disney M . Rational and modular design of potent ligands targeting the RNA that causes myotonic dystrophy 2. ACS Chem Biol. 2009; 4(5):345-55. PMC: 2748256. DOI: 10.1021/cb900025w. View

Liquori C, Ricker K, Moseley M, Jacobsen J, Kress W, Naylor S . Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001; 293(5531):864-7. DOI: 10.1126/science.1062125. View

Charlet-B N, Savkur R, Singh G, Philips A, Grice E, Cooper T . Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell. 2002; 10(1):45-53. DOI: 10.1016/s1097-2765(02)00572-5. View

Chamberlain J, Chamberlain J . Muscling in: Gene therapies for muscular dystrophy target RNA. Nat Med. 2010; 16(2):170-1. DOI: 10.1038/nm0210-170. View

ODonnell D, Zoghbi H . Trinucleotide repeat disorders in pediatrics. Curr Opin Pediatr. 1995; 7(6):715-25. DOI: 10.1097/00008480-199512000-00016. View

Pelletier R, Hamel F, Beaulieu D, Patry L, Haineault C, Tarnopolsky M . Absence of a differentiation defect in muscle satellite cells from DM2 patients. Neurobiol Dis. 2009; 36(1):181-90. DOI: 10.1016/j.nbd.2009.07.009. View

Mankodi A, Teng-Umnuay P, Krym M, Henderson D, Swanson M, Thornton C . Ribonuclear inclusions in skeletal muscle in myotonic dystrophy types 1 and 2. Ann Neurol. 2003; 54(6):760-8. DOI: 10.1002/ana.10763. View

10.

Ranum L, Day J . Myotonic dystrophy: RNA pathogenesis comes into focus. Am J Hum Genet. 2004; 74(5):793-804. PMC: 1181975. DOI: 10.1086/383590. View

11.

Gomes-Pereira M, Monckton D . Chemical modifiers of unstable expanded simple sequence repeats: what goes up, could come down. Mutat Res. 2006; 598(1-2):15-34. DOI: 10.1016/j.mrfmmm.2006.01.011. View

12.

Dhand U, Dhand R . Sleep disorders in neuromuscular diseases. Curr Opin Pulm Med. 2006; 12(6):402-8. DOI: 10.1097/01.mcp.0000245704.92311.1e. View

13.

Wang G, Kuyumcu-Martinez M, Sarma S, Mathur N, Wehrens X, Cooper T . PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1. J Clin Invest. 2009; 119(12):3797-806. PMC: 2786786. DOI: 10.1172/JCI37976. View

14.

Arambula J, Ramisetty S, Baranger A, Zimmerman S . A simple ligand that selectively targets CUG trinucleotide repeats and inhibits MBNL protein binding. Proc Natl Acad Sci U S A. 2009; 106(38):16068-73. PMC: 2752522. DOI: 10.1073/pnas.0901824106. View

15.

Ward A, Rimer M, Killian J, Dowling J, Cooper T . CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1. Hum Mol Genet. 2010; 19(18):3614-22. PMC: 2928132. DOI: 10.1093/hmg/ddq277. View

16.

Phylactou L, Darrah C, Wood M . Ribozyme-mediated trans-splicing of a trinucleotide repeat. Nat Genet. 1998; 18(4):378-81. DOI: 10.1038/ng0498-378. View

17.

Campbell C, Sherlock R, Jacob P, Blayney M . Congenital myotonic dystrophy: assisted ventilation duration and outcome. Pediatrics. 2004; 113(4):811-6. DOI: 10.1542/peds.113.4.811. View

18.

Savkur R, Philips A, Cooper T, Dalton J, Moseley M, Ranum L . Insulin receptor splicing alteration in myotonic dystrophy type 2. Am J Hum Genet. 2004; 74(6):1309-13. PMC: 1182097. DOI: 10.1086/421528. View

19.

Sioud M . Ribozyme- and siRNA-mediated mRNA degradation: a general introduction. Methods Mol Biol. 2004; 252:1-8. DOI: 10.1385/1-59259-746-7:001. View

20.

Weber Y, Roebling R, Kassubek J, Hoffmann S, Rosenbohm A, Wolf M . Comparative analysis of brain structure, metabolism, and cognition in myotonic dystrophy 1 and 2. Neurology. 2010; 74(14):1108-17. DOI: 10.1212/WNL.0b013e3181d8c35f. View