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Myotonic Dystrophies: From Genes to Novel Therapeutic Avenues

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 September 2022) | Viewed by 12025

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Special Issue Editors

Dr. Annalisa Botta

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Guest Editor

Department of Biomedicine and Prevention, Tor Vergata University of Rome, Medical Genetics Section, Rome, Italy
Interests: genetic diseases; repeat expansion diseases; biomarkers identification; epigenetics; genetic diagnosis

Prof. Dr. Arturo Lopez-Castel

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Guest Editor

Translation Genomics Group, University of Valencia, Burjassot, Spain
Interests: genetics; rare diseases; drug development; scientific photography

Special Issue Information

Dear Colleagues,

Myotonic dystrophies are multisystem, autosomal dominant inherited diseases characterized by progressive muscle weakness; myotonia; and, in many cases, cardiac and cognitive involvement. Two forms of myotonic dystrophies have been described: type 1 (DM1) is caused by a (CTG)n triplet expansion in the 3’ UTR of the DMPK gene, while type 2 (DM2) is associated with a (CCTG)n tetraplet expansion in the first intron of the CNBP gene. Despite the clinical and genetic differences between DM1 and DM2, a common toxic RNA gain-of-function has emerged as the main pathomechanism of both diseases, leading to aberrant splicing events. In recent years, the C/CUGexp-RNAs trans-dominant effects have been proven to alter other splicing-independent processes, including changes in miRNAs expression and translation efficiency, non-conventional (RAN) translation, autophagy, and apoptosis regulation. Molecular therapeutic strategies for DMs are still under investigation and can be directed specifically at the level of DNA, RNA, or protein, with the final purpose of ameliorating the effects of RNA toxicity. Currently, there is no valid treatment for DM patients who still require complex care, ranging from accurate clinical and genetic diagnosis, the investigation of pathogenic mechanisms, and the identification of early biomarkers for the appropriate design of trials.

This Special Issue of IJMS, entitled “Myotonic Dystrophies: From Genes to Novel Therapeutic Avenues”, will cover a selection of research topics related to recent advances in the genetics and cellular/molecular mechanisms of myotonic dystrophies, as well as novel therapeutic approaches. Experimental papers, commentaries, and up-to-date review articles are all welcome.

Dr. Annalisa Botta
Prof. Dr. Arturo Lopez
Guest Editors

Manuscript Submission Information

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Keywords

myotonic dystrophies
genetics
clinical diagnosis
epigenetics
molecular mechanism
biomarker identification
molecular therapies

Published Papers (5 papers)

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Research

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14 pages, 3361 KiB

Open AccessArticle

In Cis Effect of DMPK Expanded Alleles in Myotonic Dystrophy Type 1 Patients Carrying Variant Repeats at 5′ and 3′ Ends of the CTG Array

by Virginia Veronica Visconti, Elisa Macrì, Maria Rosaria D’Apice, Federica Centofanti, Roberto Massa, Giuseppe Novelli and Annalisa Botta

Int. J. Mol. Sci. 2023, 24(12), 10129; https://doi.org/10.3390/ijms241210129 - 14 Jun 2023

Cited by 1 | Viewed by 1560

Abstract

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disease caused by a CTG repeat expansion in the 3′-untranslated region (UTR) of DMPK gene. DM1 alleles containing non-CTG variant repeats (VRs) have been described, with uncertain molecular and clinical consequences. The expanded trinucleotide array is flanked by two CpG islands, and the presence of VRs could confer an additional level of epigenetic variability. This study aims to investigate the association between VR-containing DMPK alleles, parental inheritance and methylation pattern of the DM1 locus. The DM1 mutation has been characterized in 20 patients using a combination of SR-PCR, TP-PCR, modified TP-PCR and LR-PCR. Non-CTG motifs have been confirmed by Sanger sequencing. The methylation pattern of the DM1 locus was determined by bisulfite pyrosequencing. We characterized 7 patients with VRs within the CTG tract at 5′ end and 13 patients carrying non-CTG sequences at 3′ end of the DM1 expansion. DMPK alleles with VRs at 5’ end or 3’ end were invariably unmethylated upstream of the CTG expansion. Interestingly, DM1 patients with VRs at the 3′ end showed higher methylation levels in the downstream island of the CTG repeat tract, preferentially when the disease allele was maternally inherited. Our results suggest a potential correlation between VRs, parental origin of the mutation and methylation pattern of the DMPK expanded alleles. A differential CpG methylation status could play a role in the phenotypic variability of DM1 patients, representing a potentially useful diagnostic tool. Full article

(This article belongs to the Special Issue Myotonic Dystrophies: From Genes to Novel Therapeutic Avenues)

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22 pages, 2336 KiB

Open AccessArticle

Natural Compound Boldine Lessens Myotonic Dystrophy Type 1 Phenotypes in DM1 Drosophila Models, Patient-Derived Cell Lines, and HSA^LR Mice

by Mari Carmen Álvarez-Abril, Irma García-Alcover, Jordi Colonques-Bellmunt, Raquel Garijo, Manuel Pérez-Alonso, Rubén Artero and Arturo López-Castel

Int. J. Mol. Sci. 2023, 24(12), 9820; https://doi.org/10.3390/ijms24129820 - 6 Jun 2023

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Abstract

Myotonic dystrophy type 1 (DM1) is a complex rare disorder characterized by progressive muscle dysfunction, involving weakness, myotonia, and wasting, but also exhibiting additional clinical signs in multiple organs and systems. Central dysregulation, caused by an expansion of a CTG trinucleotide repeat in the DMPK gene’s 3’ UTR, has led to exploring various therapeutic approaches in recent years, a few of which are currently under clinical trial. However, no effective disease-modifying treatments are available yet. In this study, we demonstrate that treatments with boldine, a natural alkaloid identified in a large-scale Drosophila-based pharmacological screening, was able to modify disease phenotypes in several DM1 models. The most significant effects include consistent reduction in nuclear RNA foci, a dynamic molecular hallmark of the disease, and noteworthy anti-myotonic activity. These results position boldine as an attractive new candidate for therapy development in DM1. Full article

(This article belongs to the Special Issue Myotonic Dystrophies: From Genes to Novel Therapeutic Avenues)

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Review

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13 pages, 1357 KiB

Open AccessReview

Application of Antisense Conjugates for the Treatment of Myotonic Dystrophy Type 1

by Jessica Stoodley, Francisco Vallejo-Bedia, David Seone-Miraz, Manuel Debasa-Mouce, Matthew J. A. Wood and Miguel A. Varela

Int. J. Mol. Sci. 2023, 24(3), 2697; https://doi.org/10.3390/ijms24032697 - 31 Jan 2023

Cited by 6 | Viewed by 3410

Abstract

Myotonic dystrophy type 1 (DM1) is one of the most common muscular dystrophies and can be potentially treated with antisense therapy decreasing mutant DMPK, targeting miRNAs or their binding sites or via a blocking mechanism for MBNL1 displacement from the repeats. Unconjugated antisense molecules are able to correct the disease phenotype in mouse models, but they show poor muscle penetration upon systemic delivery in DM1 patients. In order to overcome this challenge, research has focused on the improvement of the therapeutic window and biodistribution of antisense therapy using bioconjugation to lipids, cell penetrating peptides or antibodies. Antisense conjugates are able to induce the long-lasting correction of DM1 pathology at both molecular and functional levels and also efficiently penetrate hard-to-reach tissues such as cardiac muscle. Delivery to the CNS at clinically relevant levels remains challenging and the use of alternative administration routes may be necessary to ameliorate some of the symptoms experienced by DM1 patients. With several antisense therapies currently in clinical trials, the outlook for achieving a clinically approved treatment for patients has never looked more promising. Full article

(This article belongs to the Special Issue Myotonic Dystrophies: From Genes to Novel Therapeutic Avenues)

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10 pages, 252 KiB

Open AccessReview

Fluid Biomarkers of Central Nervous System (CNS) Involvement in Myotonic Dystrophy Type 1 (DM1)

by Salvatore Rossi and Gabriella Silvestri

Int. J. Mol. Sci. 2023, 24(3), 2204; https://doi.org/10.3390/ijms24032204 - 22 Jan 2023

Cited by 2 | Viewed by 1515

Abstract

Myotonic dystrophy type 1 (DM1), commonly known as Steinert’s disease (OMIM #160900), is the most common muscular dystrophy among adults, caused by an unstable expansion of a CTG trinucleotide repeat in the 3′ untranslated region (UTR) of DMPK. Besides skeletal muscle, central nervous system (CNS) involvement is one of the core manifestations of DM1, whose relevant cognitive, behavioral, and affective symptoms deeply affect quality of life of DM1 patients, and that, together with muscle and heart, may profoundly influence the global disease burden and overall prognosis. Therefore, CNS should be also included among the main targets for future therapeutic developments in DM1, and, in this regard, identifying a cost-effective, easily accessible, and sensitive diagnostic and monitoring biomarker of CNS involvement in DM1 represents a relevant issue to be addressed. In this mini review, we will discuss all the papers so far published exploring the usefulness of both cerebrospinal fluid (CSF) and blood-based biomarkers of CNS involvement in DM1. Globally, the results of these studies are quite consistent on the value of CSF and blood Neurofilament Light Chain (NfL) as a biomarker of CNS involvement, with less robust results regarding levels of tau protein or amyloid-beta. Full article

(This article belongs to the Special Issue Myotonic Dystrophies: From Genes to Novel Therapeutic Avenues)

28 pages, 1456 KiB

Open AccessReview

Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1

by Thiéry De Serres-Bérard, Siham Ait Benichou, Dominic Jauvin, Mohamed Boutjdir, Jack Puymirat and Mohamed Chahine

Int. J. Mol. Sci. 2022, 23(21), 13359; https://doi.org/10.3390/ijms232113359 - 1 Nov 2022

Cited by 8 | Viewed by 3523

Abstract

Myotonic dystrophy type 1 (DM1) is a dominant genetic disease in which the expansion of long CTG trinucleotides in the 3′ UTR of the myotonic dystrophy protein kinase (DMPK) gene results in toxic RNA gain-of-function and gene mis-splicing affecting mainly the muscles, the heart, and the brain. The CUG-expanded transcripts are a suitable target for the development of antisense oligonucleotide (ASO) therapies. Various chemical modifications of the sugar-phosphate backbone have been reported to significantly enhance the affinity of ASOs for RNA and their resistance to nucleases, making it possible to reverse DM1-like symptoms following systemic administration in different transgenic mouse models. However, specific tissue delivery remains to be improved to achieve significant clinical outcomes in humans. Several strategies, including ASO conjugation to cell-penetrating peptides, fatty acids, or monoclonal antibodies, have recently been shown to improve potency in muscle and cardiac tissues in mice. Moreover, intrathecal administration of ASOs may be an advantageous complementary administration route to bypass the blood-brain barrier and correct defects of the central nervous system in DM1. This review describes the evolution of the chemical design of antisense oligonucleotides targeting CUG-expanded mRNAs and how recent advances in the field may be game-changing by forwarding laboratory findings into clinical research and treatments for DM1 and other microsatellite diseases. Full article

(This article belongs to the Special Issue Myotonic Dystrophies: From Genes to Novel Therapeutic Avenues)

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