Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Sep 23

PMID 36142405

Authors

Lubov Timchenko

Affiliations

Soon will be listed here.

Abstract

Myotonic Dystrophies type 1 (DM1) and type 2 (DM2) are complex multisystem diseases without disease-based therapies. These disorders are caused by the expansions of unstable CTG (DM1) and CCTG (DM2) repeats outside of the coding regions of the disease genes: in DM1 and in DM2. Multiple clinical and molecular studies provided a consensus for DM1 pathogenesis, showing that the molecular pathophysiology of DM1 is associated with the toxicity of RNA CUG repeats, which cause multiple disturbances in RNA metabolism in patients' cells. As a result, splicing, translation, RNA stability and transcription of multiple genes are misregulated in DM1 cells. While mutant CCUG repeats are the main cause of DM2, additional factors might play a role in DM2 pathogenesis. This review describes current progress in the translation of mechanistic knowledge in DM1 and DM2 to clinical trials, with a focus on the development of disease-specific therapies for patients with adult forms of DM1 and congenital DM1 (CDM1).

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References

Reddy K, Jenquin J, McConnell O, Cleary J, Richardson J, Pinto B . A CTG repeat-selective chemical screen identifies microtubule inhibitors as selective modulators of toxic CUG RNA levels. Proc Natl Acad Sci U S A. 2019; 116(42):20991-21000. PMC: 6800345. DOI: 10.1073/pnas.1901893116. View

Jones K, Wei C, Iakova P, Bugiardini E, Schneider-Gold C, Meola G . GSK3β mediates muscle pathology in myotonic dystrophy. J Clin Invest. 2012; 122(12):4461-72. PMC: 3533547. DOI: 10.1172/JCI64081. View

Izzo M, Battistini J, Provenzano C, Martelli F, Cardinali B, Falcone G . Molecular Therapies for Myotonic Dystrophy Type 1: From Small Drugs to Gene Editing. Int J Mol Sci. 2022; 23(9). PMC: 9101876. DOI: 10.3390/ijms23094622. View

Xing X, Kumari A, Brown J, Brook J . Disrupting the Molecular Pathway in Myotonic Dystrophy. Int J Mol Sci. 2021; 22(24). PMC: 8708683. DOI: 10.3390/ijms222413225. View

Deng J, Guan X, Zhu Y, Deng H, Li G, Guo Y . Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Model. J Pers Med. 2022; 12(3). PMC: 8948895. DOI: 10.3390/jpm12030385. View

Zu T, Cleary J, Liu Y, Banez-Coronel M, Bubenik J, Ayhan F . RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2. Neuron. 2017; 95(6):1292-1305.e5. PMC: 5951173. DOI: 10.1016/j.neuron.2017.08.039. View

Klein A, Varela M, Arandel L, Holland A, Naouar N, Arzumanov A . Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice. J Clin Invest. 2019; 129(11):4739-4744. PMC: 6819114. DOI: 10.1172/JCI128205. View

Benhamou R, Angelbello A, Wang E, Disney M . A Toxic RNA Catalyzes the Cellular Synthesis of Its Own Inhibitor, Shunting It to Endogenous Decay Pathways. Cell Chem Biol. 2020; 27(2):223-231.e4. PMC: 7081931. DOI: 10.1016/j.chembiol.2020.01.003. View

Day J, Ricker K, Jacobsen J, Rasmussen L, Dick K, Kress W . Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology. 2003; 60(4):657-64. DOI: 10.1212/01.wnl.0000054481.84978.f9. View

10.

Renton A, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs J . A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011; 72(2):257-68. PMC: 3200438. DOI: 10.1016/j.neuron.2011.09.010. View

11.

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

12.

Armas P, Coux G, Weiner A, Calcaterra N . What's new about CNBP? Divergent functions and activities for a conserved nucleic acid binding protein. Biochim Biophys Acta Gen Subj. 2021; 1865(11):129996. DOI: 10.1016/j.bbagen.2021.129996. View

13.

Bargiela A, Sabater-Arcis M, Espinosa-Espinosa J, Zulaica M, de Munain A, Artero R . Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models. Proc Natl Acad Sci U S A. 2019; 116(50):25203-25213. PMC: 6911202. DOI: 10.1073/pnas.1820297116. View

14.

Sofola O, Jin P, Qin Y, Duan R, Liu H, de Haro M . RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron. 2007; 55(4):565-71. PMC: 2215388. DOI: 10.1016/j.neuron.2007.07.021. View

15.

Sellier C, Cerro-Herreros E, Blatter M, Freyermuth F, Gaucherot A, Ruffenach F . rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences. Nat Commun. 2018; 9(1):2009. PMC: 5964235. DOI: 10.1038/s41467-018-04370-x. View

16.

Garcia-Puga M, Saenz-Antonanzas A, Fernandez-Torron R, de Munain A, Matheu A . Myotonic Dystrophy type 1 cells display impaired metabolism and mitochondrial dysfunction that are reversed by metformin. Aging (Albany NY). 2020; 12(7):6260-6275. PMC: 7185118. DOI: 10.18632/aging.103022. View

17.

Swinnen B, Robberecht W, Van Den Bosch L . RNA toxicity in non-coding repeat expansion disorders. EMBO J. 2019; 39(1):e101112. PMC: 6939197. DOI: 10.15252/embj.2018101112. View

18.

Savkur R, Philips A, Cooper T . Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet. 2001; 29(1):40-7. DOI: 10.1038/ng704. View

19.

TANEJA K, McCurrach M, Schalling M, Housman D, Singer R . Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol. 1995; 128(6):995-1002. PMC: 2120416. DOI: 10.1083/jcb.128.6.995. View

20.

Wei C, Stock L, Schneider-Gold C, Sommer C, Timchenko N, Timchenko L . Reduction of Cellular Nucleic Acid Binding Protein Encoded by a Myotonic Dystrophy Type 2 Gene Causes Muscle Atrophy. Mol Cell Biol. 2018; 38(14). PMC: 6024164. DOI: 10.1128/MCB.00649-17. View