{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:28:35Z","timestamp":1760236115025,"version":"build-2065373602"},"reference-count":133,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T00:00:00Z","timestamp":1634860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG21877"],"award-info":[{"award-number":["IG21877"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Neuromuscular disorders represent multifaceted abnormal conditions, with little or no cure, leading to patient deaths from complete muscle wasting and atrophy. Despite strong efforts in the past decades, development of effective treatments is still urgently needed. Advent of next-generation sequencing technologies has allowed identification of novel genes and mutations associated with neuromuscular pathologies, highlighting splicing defects as essential players. Deciphering the significance and relative contributions of defective RNA metabolism will be instrumental to address and counteract these malignancies. We review here recent progress on the role played by alternative splicing in ensuring functional neuromuscular junctions (NMJs), and its involvement in the pathogenesis of NMJ-related neuromuscular disorders, with particular emphasis on congenital myasthenic syndromes and muscular dystrophies. We will also discuss novel strategies based on oligonucleotides designed to bind their cognate sequences in the RNA or targeting intermediary of mRNA metabolism. These efforts resulted in several chemical classes of RNA molecules that have recently proven to be clinically effective, more potent and better tolerated than previous strategies.<\/jats:p>","DOI":"10.3390\/cells10112850","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T09:18:09Z","timestamp":1634894289000},"page":"2850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing"],"prefix":"10.3390","volume":"10","author":[{"given":"Veronica","family":"Verdile","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Fondazione Santa Lucia, CERC, 00143 Rome, Italy"},{"name":"Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis 6, 00135 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gloria","family":"Guizzo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Fondazione Santa Lucia, CERC, 00143 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Ferrante","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Fondazione Santa Lucia, CERC, 00143 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5324-0903","authenticated-orcid":false,"given":"Maria Paola","family":"Paronetto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Neurobiology, Fondazione Santa Lucia, CERC, 00143 Rome, Italy"},{"name":"Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Piazza Lauro de Bosis 6, 00135 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1152\/physrev.00033.2014","article-title":"Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting","volume":"95","author":"Tintignac","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/nrm2024","article-title":"Molecular mechanisms of muscular dystrophies: Old and new players","volume":"7","author":"Davies","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1097\/WCO.0000000000000848","article-title":"Hereditary motor neuropathies","volume":"33","author":"Dohrn","year":"2020","journal-title":"Curr. Opin. Neurol"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.cell.2007.02.035","article-title":"Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals","volume":"129","author":"Fox","year":"2007","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/377232a0","article-title":"Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice","volume":"377","author":"Gautam","year":"1995","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S0092-8674(00)81253-2","article-title":"Defective neuromuscular synaptogenesis in agrin-deficient mutant mice","volume":"85","author":"Gautam","year":"1996","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/S0092-8674(00)81251-9","article-title":"The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo","volume":"85","author":"DeChiara","year":"1996","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1517\/14728214.2012.691965","article-title":"Emerging drugs for Duchenne muscular dystrophy","volume":"17","author":"Malik","year":"2012","journal-title":"Expert Opin. Emerg. Drugs"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S1474-4422(18)30025-5","article-title":"Diagnosis and management of Duchenne muscular dystrophy, part 2: Respiratory, cardiac, bone health, and orthopaedic management","volume":"17","author":"Birnkrant","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1196\/annals.1254.002","article-title":"Neurophysiology of the neuromuscular junction: Overview","volume":"998","author":"Ruff","year":"2003","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0896-6273(00)80894-6","article-title":"Maturation and maintenance of the neuromuscular synapse: Genetic evidence for roles of the dystrophin--glycoprotein complex","volume":"25","author":"Grady","year":"2000","journal-title":"Neuron"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1083\/jcb.150.6.1385","article-title":"Absence of alpha-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin","volume":"150","author":"Adams","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"134833","DOI":"10.1016\/j.neulet.2020.134833","article-title":"The role of the dystrophin glycoprotein complex on the neuromuscular system","volume":"722","author":"Belhasan","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.nmd.2009.02.011","article-title":"Aberrant development of neuromuscular junctions in glycosylation-defective Large(myd) mice","volume":"19","author":"Herbst","year":"2009","journal-title":"Neuromuscul. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00018-014-1663-7","article-title":"Recovery of altered neuromuscular junction morphology and muscle function in mdx mice after injury","volume":"72","author":"Pratt","year":"2015","journal-title":"Cell Mol. Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.mcn.2005.10.020","article-title":"Synapse disassembly and formation of new synapses in postnatal muscle upon conditional inactivation of MuSK","volume":"31","author":"Hesser","year":"2006","journal-title":"Mol. Cell Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S1474-4422(14)70201-7","article-title":"Congenital myasthenic syndromes: Pathogenesis, diagnosis, and treatment","volume":"14","author":"Engel","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13023-019-1025-5","article-title":"Congenital myasthenic syndromes","volume":"14","author":"Finsterer","year":"2019","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41572-021-00248-3","article-title":"Duchenne muscular dystrophy","volume":"7","author":"Duan","year":"2021","journal-title":"Nat. Rev. Dis Primers"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"368","DOI":"10.3389\/fneur.2018.00368","article-title":"Abnormalities in Skeletal Muscle Myogenesis, Growth, and Regeneration in Myotonic Dystrophy","volume":"9","author":"Ausems","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.stem.2018.03.022","article-title":"The Dystrophin Glycoprotein Complex Regulates the Epigenetic Activation of Muscle Stem Cell Commitment","volume":"22","author":"Chang","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1038\/nm.3990","article-title":"Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division","volume":"21","author":"Dumont","year":"2015","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s13052-016-0289-9","article-title":"Congenital muscular dystrophy: From muscle to brain","volume":"42","author":"Falsaperla","year":"2016","journal-title":"Ital. J. Pediatr."},{"key":"ref_24","first-page":"1619","article-title":"The Dystrophinopathies","volume":"25","author":"Thangarajh","year":"2019","journal-title":"Continuum"},{"key":"ref_25","first-page":"179","article-title":"Causes of clinical variability in Duchenne and Becker muscular dystrophies and implications for exon skipping therapies","volume":"39","author":"Hoffman","year":"2020","journal-title":"Acta Myol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/humu.21426","article-title":"Nonsense mutation-associated Becker muscular dystrophy: Interplay between exon definition and splicing regulatory elements within the DMD gene","volume":"32","author":"Flanigan","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1002\/mus.26750","article-title":"Neurodevelopmental, behavioral, and emotional symptoms in Becker muscular dystrophy","volume":"61","author":"Lambert","year":"2020","journal-title":"Muscle Nerve"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1093\/hmg\/ddab108","article-title":"Modeling muscle regeneration in RNA toxicity mice","volume":"30","author":"Yadava","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nature08909","article-title":"Expansion of the eukaryotic proteome by alternative splicing","volume":"463","author":"Nilsen","year":"2010","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/nrg3778","article-title":"Context-dependent control of alternative splicing by RNA-binding proteins","volume":"15","author":"Fu","year":"2014","journal-title":"Nat. Rev. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/ng1159","article-title":"Alternative splicing in the human, mouse and rat genomes is associated with an increased frequency of exon creation and\/or loss","volume":"34","author":"Modrek","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3754","DOI":"10.1093\/nar\/gkf492","article-title":"Genome-wide detection of tissue-specific alternative splicing in the human transcriptome","volume":"30","author":"Xu","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/nrg2673","article-title":"RNA processing and its regulation: Global insights into biological networks","volume":"11","author":"Licatalosi","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/35067589","article-title":"Acetylcholinesterase--new roles for an old actor","volume":"2","author":"Soreq","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1006\/mcne.2001.0965","article-title":"Molecular determinants of metabotropic glutamate receptor 1B trafficking","volume":"17","author":"Chan","year":"2001","journal-title":"Mol. Cell Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1016\/j.cell.2013.02.034","article-title":"Dynamic integration of splicing within gene regulatory pathways","volume":"152","author":"Braunschweig","year":"2013","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.sbi.2013.03.006","article-title":"Alternative splicing of intrinsically disordered regions and rewiring of protein interactions","volume":"23","author":"Buljan","year":"2013","journal-title":"Curr. Opin. Struct Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/978-3-662-09728-1_7","article-title":"Alternative pre-mRNA splicing and neuronal function","volume":"31","author":"Black","year":"2003","journal-title":"Prog Mol. Subcell. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nrm.2017.27","article-title":"Alternative splicing as a regulator of development and tissue identity","volume":"18","author":"Baralle","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/nature07509","article-title":"Alternative isoform regulation in human tissue transcriptomes","volume":"456","author":"Wang","year":"2008","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"170185","DOI":"10.1038\/sdata.2017.185","article-title":"An RNA-Seq atlas of gene expression in mouse and rat normal tissues","volume":"4","author":"Leparc","year":"2017","journal-title":"Sci. Data"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1126\/science.1228186","article-title":"Evolutionary dynamics of gene and isoform regulation in Mammalian tissues","volume":"338","author":"Merkin","year":"2012","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7651","DOI":"10.1093\/nar\/gkq614","article-title":"Global regulation of alternative splicing during myogenic differentiation","volume":"38","author":"Bland","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e27192","DOI":"10.7554\/eLife.27192","article-title":"Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions","volume":"6","author":"Brinegar","year":"2017","journal-title":"eLife"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nbt.1621","article-title":"Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation","volume":"28","author":"Trapnell","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/nature09000","article-title":"Deciphering the splicing code","volume":"465","author":"Barash","year":"2010","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1101\/gr.220962.117","article-title":"An atlas of alternative splicing profiles and functional associations reveals new regulatory programs and genes that simultaneously express multiple major isoforms","volume":"27","author":"Tapial","year":"2017","journal-title":"Genome Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13395-018-0152-3","article-title":"Diversification of the muscle proteome through alternative splicing","volume":"8","author":"Nakka","year":"2018","journal-title":"Skelet Muscle"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1101\/gad.2.12a.1627","article-title":"Alternative splicing of tropomyosin pre-mRNAs in vitro and in vivo","volume":"2","author":"Helfman","year":"1988","journal-title":"Genes Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1101\/gad.5.4.642","article-title":"Alpha-tropomyosin mutually exclusive exon selection: Competition between branchpoint\/polypyrimidine tracts determines default exon choice","volume":"5","author":"Mullen","year":"1991","journal-title":"Genes Dev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.cub.2017.01.018","article-title":"Tropomyosin Isoforms Specify Functionally Distinct Actin Filament Populations In Vitro","volume":"27","author":"Gateva","year":"2017","journal-title":"Curr. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1146\/annurev.bb.16.060187.002535","article-title":"Structural aspects of troponin-tropomyosin regulation of skeletal muscle contraction","volume":"16","author":"Zot","year":"1987","journal-title":"Annu Rev. Biophys Biophys. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1016\/j.celrep.2016.10.072","article-title":"Alternative Splicing of Four Trafficking Genes Regulates Myofiber Structure and Skeletal Muscle Physiology","volume":"17","author":"Giudice","year":"2016","journal-title":"Cell Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.molmed.2012.06.006","article-title":"Pre-mRNA splicing in disease and therapeutics","volume":"18","author":"Singh","year":"2012","journal-title":"Trends Mol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.jneuroim.2008.05.030","article-title":"The congenital myasthenic syndromes","volume":"201\u2013202","author":"Palace","year":"2008","journal-title":"J. Neuroimmunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"13208","DOI":"10.1038\/srep13208","article-title":"SRSF1 and hnRNP H antagonistically regulate splicing of COLQ exon 16 in a congenital myasthenic syndrome","volume":"5","author":"Rahman","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_57","first-page":"854","article-title":"Congenital myasthenic syndromes:gene mutations","volume":"13","author":"Ohno","year":"2003","journal-title":"Neuromuscul. Disord."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3765","DOI":"10.1093\/hmg\/dds198","article-title":"The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome","volume":"21","author":"Cossins","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1212\/01.wnl.0000233837.79459.40","article-title":"Impaired receptor clustering in congenital myasthenic syndrome with novel RAPSN mutations","volume":"67","author":"Baumeister","year":"2006","journal-title":"Neurology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1101\/gr.6320607","article-title":"Functional persistence of exonized mammalian-wide interspersed repeat elements (MIRs)","volume":"17","author":"Krull","year":"2007","journal-title":"Genome Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4022","DOI":"10.1093\/hmg\/ddn305","article-title":"hnRNP H enhances skipping of a nonfunctional exon P3A in CHRNA1 and a mutation disrupting its binding causes congenital myasthenic syndrome","volume":"17","author":"Masuda","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6841","DOI":"10.1038\/srep06841","article-title":"HnRNP C, YB-1 and hnRNP L coordinately enhance skipping of human MUSK exon 10 to generate a Wnt-insensitive MuSK isoform","volume":"4","author":"Nasrin","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1002\/humu.22758","article-title":"The TREAT-NMD DMD Global Database: Analysis of more than 7,000 Duchenne muscular dystrophy mutations","volume":"36","author":"Bladen","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_64","first-page":"835","article-title":"Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications","volume":"45","author":"Grootscholten","year":"1989","journal-title":"Am. J. Hum. Genet."},{"key":"ref_65","first-page":"498","article-title":"The molecular basis for Duchenne versus Becker muscular dystrophy: Correlation of severity with type of deletion","volume":"45","author":"Koenig","year":"1989","journal-title":"Am. J. Hum. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/S1474-4422(03)00585-4","article-title":"Dystrophin and mutations: One gene, several proteins, multiple phenotypes","volume":"2","author":"Muntoni","year":"2003","journal-title":"Lancet Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1126\/science.3055295","article-title":"Frame-shift deletions in patients with Duchenne and Becker muscular dystrophy","volume":"242","author":"Malhotra","year":"1988","journal-title":"Science"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"10488","DOI":"10.1038\/ncomms10488","article-title":"The lack of the Celf2a splicing factor converts a Duchenne genotype into a Becker phenotype","volume":"7","author":"Martone","year":"2016","journal-title":"Nat. Commun"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/jhg.2014.36","article-title":"A novel splicing silencer generated by DMD exon 45 deletion junction could explain upstream exon 44 skipping that modifies dystrophinopathy","volume":"59","author":"Dwianingsih","year":"2014","journal-title":"J. Hum. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1172\/JCI119757","article-title":"Disruption of the splicing enhancer sequence within exon 27 of the dystrophin gene by a nonsense mutation induces partial skipping of the exon and is responsible for Becker muscular dystrophy","volume":"100","author":"Shiga","year":"1997","journal-title":"J. Clin. Invest."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S1474-4422(16)30078-3","article-title":"Duchenne muscular dystrophy: Meeting the therapeutic challenge","volume":"15","author":"Flanigan","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/humu.20422","article-title":"Protein- and mRNA-based phenotype-genotype correlations in DMD\/BMD with point mutations and molecular basis for BMD with nonsense and frameshift mutations in the DMD gene","volume":"28","author":"Deburgrave","year":"2007","journal-title":"Hum. Mutat."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/nrg.2016.46","article-title":"Lessons from non-canonical splicing","volume":"17","author":"Sibley","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1086\/301952","article-title":"A novel Alu-like element rearranged in the dystrophin gene causes a splicing mutation in a family with X-linked dilated cardiomyopathy","volume":"63","author":"Ferlini","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1038\/ejhg.2012.51","article-title":"Comprehensive oligonucleotide array-comparative genomic hybridization analysis: New insights into the molecular pathology of the DMD gene","volume":"20","author":"Ishmukhametova","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1002\/mgg3.144","article-title":"Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient","volume":"3","author":"Greer","year":"2015","journal-title":"Mol. Genet. Genomic. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1126\/science.289.5485.1769","article-title":"Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat","volume":"289","author":"Mankodi","year":"2000","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3079","DOI":"10.1093\/hmg\/ddh327","article-title":"Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons","volume":"13","author":"Jiang","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4439","DOI":"10.1093\/emboj\/19.17.4439","article-title":"Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy","volume":"19","author":"Miller","year":"2000","journal-title":"EMBO J."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5773","DOI":"10.1074\/jbc.M410781200","article-title":"MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1","volume":"280","author":"Dansithong","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1093\/nar\/29.13.2766","article-title":"In vivo co-localisation of MBNL protein with DMPK expanded-repeat transcripts","volume":"29","author":"Fardaei","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1002\/j.1460-2075.1990.tb07416.x","article-title":"Functionally distinct insulin receptors generated by tissue-specific alternative splicing","volume":"9","author":"Mosthaf","year":"1990","journal-title":"EMBO J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/0006-291X(91)90639-O","article-title":"The two isotypes of the human insulin receptor (HIR-A and HIR-B) follow different internalization kinetics","volume":"177","author":"Vogt","year":"1991","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/ng704","article-title":"Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy","volume":"29","author":"Savkur","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"7205","DOI":"10.1038\/ncomms8205","article-title":"Abnormal splicing switch of DMD\u2019s penultimate exon compromises muscle fibre maintenance in myotonic dystrophy","volume":"6","author":"Rau","year":"2015","journal-title":"Nat. Commun"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1161\/01.RES.0000126574.61061.25","article-title":"The dystrophin glycoprotein complex: Signaling strength and integrity for the sarcolemma","volume":"94","author":"Lapidos","year":"2004","journal-title":"Circ. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1016\/S0960-9822(00)00760-0","article-title":"Alternative splicing of dystrobrevin regulates the stoichiometry of syntrophin binding to the dystrophin protein complex","volume":"10","author":"Newey","year":"2000","journal-title":"Curr. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1212\/01.wnl.0000302174.08951.cf","article-title":"Aberrantly spliced alpha-dystrobrevin alters alpha-syntrophin binding in myotonic dystrophy type 1","volume":"70","author":"Nakamori","year":"2008","journal-title":"Neurology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1093\/hmg\/ddr568","article-title":"Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of Ca(V)1.1 calcium channel","volume":"21","author":"Tang","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1093\/hmg\/ddi223","article-title":"Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic\/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1","volume":"14","author":"Kimura","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_91","first-page":"1547","article-title":"Restricting calcium currents is required for correct fiber type specification in skeletal muscle","volume":"143","author":"Sultana","year":"2016","journal-title":"Development"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1111\/nan.12076","article-title":"Alternative splicing alterations of Ca2+ handling genes are associated with Ca2+ signal dysregulation in myotonic dystrophy type 1 (DM1) and type 2 (DM2) myotubes","volume":"40","author":"Santoro","year":"2014","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1146\/annurev-neuro-070918-050501","article-title":"Antisense Oligonucleotide Therapies for Neurodegenerative Diseases","volume":"42","author":"Bennett","year":"2019","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1016\/j.drudis.2018.08.004","article-title":"RNA-mediated therapies in myotonic dystrophy","volume":"23","author":"Overby","year":"2018","journal-title":"Drug Discov. Today"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"35","DOI":"10.14304\/SURYA.JPR.V4N7.5","article-title":"RNA therapeutics: RNAi and antisense mechanisms and clinical applications","volume":"4","author":"Chery","year":"2016","journal-title":"Postdoc J."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Raaijmakers, R.H.L., Ripken, L., Ausems, C.R.M., and Wansink, D.G. (2019). CRISPR\/Cas Applications in Myotonic Dystrophy: Expanding Opportunities. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20153689"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1038\/s41467-018-04892-4","article-title":"miR-23b and miR-218 silencing increase Muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models","volume":"9","author":"Moreno","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/ana.24555","article-title":"Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy","volume":"79","author":"Mendell","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1515\/tnsci-2017-0001","article-title":"ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy","volume":"8","author":"Ottesen","year":"2017","journal-title":"Transl. Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1146\/annurev.pharmtox.010909.105654","article-title":"RNA targeting therapeutics: Molecular mechanisms of antisense oligonucleotides as a therapeutic platform","volume":"50","author":"Bennett","year":"2010","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1146\/annurev-pharmtox-010716-104846","article-title":"Pharmacology of Antisense Drugs","volume":"57","author":"Bennett","year":"2017","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.bbrc.2015.04.035","article-title":"Antisense oligonucleotide-mediated exon skipping of CHRNA1 pre-mRNA as potential therapy for Congenital Myasthenic Syndromes","volume":"461","author":"Tei","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/S0140-6736(11)61028-3","article-title":"Exon-skipping therapy for Duchenne muscular dystrophy","volume":"378","author":"Nakamura","year":"2011","journal-title":"Lancet"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/S0140-6736(11)60756-3","article-title":"Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: An open-label, phase 2, dose-escalation study","volume":"378","author":"Cirak","year":"2011","journal-title":"Lancet"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1007\/s40265-016-0657-1","article-title":"Eteplirsen: First Global Approval","volume":"76","author":"Syed","year":"2016","journal-title":"Drugs"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1358\/dot.2016.52.3.2473590","article-title":"Duchenne muscular dystrophy drugs face tough path to approval","volume":"52","author":"Hodgkinson","year":"2016","journal-title":"Drugs Today"},{"key":"ref_107","unstructured":"(2020, August 28). Sarepta Therapeutics Announces Positive Expression Results from the Casimersen (SRP-4045) Arm of the ESSENCE Study. Available online: https:\/\/investorrelations.sarepta.com\/news-releases\/news-release-details\/sarepta-therapeuticsannounces-positive-expression-results."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1007\/s40265-021-01512-2","article-title":"Casimersen: First Approval","volume":"81","author":"Shirley","year":"2021","journal-title":"Drugs"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e2270","DOI":"10.1212\/WNL.0000000000009233","article-title":"Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy","volume":"94","author":"Frank","year":"2020","journal-title":"Neurology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s40265-020-01267-2","article-title":"Golodirsen: First Approval","volume":"80","author":"Heo","year":"2020","journal-title":"Drugs"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1007\/s40265-020-01339-3","article-title":"Viltolarsen: First Approval","volume":"80","author":"Dhillon","year":"2020","journal-title":"Drugs"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1126\/science.1104297","article-title":"Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping","volume":"306","author":"Goyenvalle","year":"2004","journal-title":"Science"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.tig.2011.02.004","article-title":"Genetic therapies for RNA mis-splicing diseases","volume":"27","author":"Hammond","year":"2011","journal-title":"Trends Genet."},{"key":"ref_114","unstructured":"(2021, October 10). AAV9 U7snRNA Gene Therapy to Treat Boys with DMD Exon 2 Duplications, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04240314."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1093\/hmg\/ddl132","article-title":"Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy","volume":"15","author":"Lin","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nature11362","article-title":"Targeting nuclear RNA for in vivo correction of myotonic dystrophy","volume":"488","author":"Wheeler","year":"2012","journal-title":"Nature"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.omtn.2020.11.014","article-title":"Antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy","volume":"23","author":"Hu","year":"2021","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1126\/science.1225829","article-title":"A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity","volume":"337","author":"Jinek","year":"2012","journal-title":"Science"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1258096","DOI":"10.1126\/science.1258096","article-title":"Genome editing. The new frontier of genome engineering with CRISPR-Cas9","volume":"346","author":"Doudna","year":"2014","journal-title":"Science"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"8275","DOI":"10.1093\/nar\/gky548","article-title":"Efficient CRISPR\/Cas9-mediated editing of trinucleotide repeat expansion in myotonic dystrophy patient-derived iPS and myogenic cells","volume":"46","author":"Dastidar","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.omtn.2017.10.006","article-title":"CRISPR\/Cas9-Mediated Deletion of CTG Expansions Recovers Normal Phenotype in Myogenic Cells Derived from Myotonic Dystrophy 1 Patients","volume":"9","author":"Provenzano","year":"2017","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1016\/j.ymthe.2018.09.003","article-title":"Therapeutic Genome Editing for Myotonic Dystrophy Type 1 Using CRISPR\/Cas9","volume":"26","author":"Wang","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1080\/15476286.2017.1279787","article-title":"Antisense transcription of the myotonic dystrophy locus yields low-abundant RNAs with and without (CAG)n repeat","volume":"14","author":"Gudde","year":"2017","journal-title":"RNA Biol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1016\/j.ymthe.2019.05.021","article-title":"Genome Editing of Expanded CTG Repeats within the Human DMPK Gene Reduces Nuclear RNA Foci in the Muscle of DM1 Mice","volume":"27","author":"Poulard","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/s41551-020-00607-7","article-title":"The sustained expression of Cas9 targeting toxic RNAs reverses disease phenotypes in mouse models of myotonic dystrophy type 1","volume":"5","author":"Batra","year":"2021","journal-title":"Nat. Biomed. Eng."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"11748","DOI":"10.1073\/pnas.0604970103","article-title":"Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy","volume":"103","author":"Kanadia","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/nm.3487","article-title":"MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1","volume":"20","author":"Schober","year":"2014","journal-title":"Nat. Med."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.omtn.2020.07.021","article-title":"Therapeutic Potential of AntagomiR-23b for Treating Myotonic Dystrophy","volume":"21","author":"Overby","year":"2020","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1016\/j.drudis.2021.03.024","article-title":"Myotonic dystrophy type 1 drug development: A pipeline toward the market","volume":"26","author":"Artero","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1001\/jama.280.10.871-JMN0909-6-1","article-title":"First \u201cantisense\u201d drug will treat CMV retinitis","volume":"280","author":"Marwick","year":"1998","journal-title":"JAMA"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s41582-018-0033-8","article-title":"Why dystrophin quantification is key in the eteplirsen saga","volume":"14","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1089\/nat.2017.0665","article-title":"FDA Approval of Nusinersen for Spinal Muscular Atrophy Makes 2016 the Year of Splice Modulating Oligonucleotides","volume":"27","year":"2017","journal-title":"Nucleic Acid. Ther."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s00415-018-9124-0","article-title":"Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients","volume":"266","author":"Wurster","year":"2019","journal-title":"J. Neurol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/2850\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:21:24Z","timestamp":1760167284000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/2850"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,22]]},"references-count":133,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cells10112850"],"URL":"https:\/\/doi.org\/10.3390\/cells10112850","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2021,10,22]]}}}