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dc.contributor.authorCerro Herreros, Estefanía
dc.contributor.authorGonzález Martínez, Irene
dc.contributor.authorMoreno, Nerea
dc.contributor.authorEspinosa Espinosa, Jorge
dc.contributor.authorFernández Costa, Juan M.
dc.contributor.authorColom Rodrigo, Anna
dc.contributor.authorOverby, Sarah J.
dc.contributor.authorSeoane Miraz, David
dc.contributor.authorPoyatos García, Javier
dc.contributor.authorVilchez, Juan J.
dc.contributor.authorLópez de Munain Arregui, Adolfo José
dc.contributor.authorVarela, Miguel A.
dc.contributor.authorWood, Matthew J.
dc.contributor.authorPérez Alonso, Manuel
dc.contributor.authorLlamusí, Beatriz
dc.contributor.authorArtero, Rubén
dc.date.accessioned2021-10-25T07:42:18Z
dc.date.available2021-10-25T07:42:18Z
dc.date.issued2021-12-03
dc.identifier.citationMolecular Therapy-Nucleic Acids 26 : 174-191 (2021)es_ES
dc.identifier.issn2162-2531
dc.identifier.urihttp://hdl.handle.net/10810/53616
dc.description.abstractMyotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease symptoms such as muscle weakness and atrophy and myotonia, yet upregulation of endogenous MBNL1 levels may compensate for this sequestration. Having previously demonstrated that antisense oligonucleotides against miR-218 boost MBNL1 expression and rescue phenotypes in disease models, here we provide preclinical characterization of an antagomiR-218 molecule using the HSALR mouse model and patient-derived myotubes. In HSALR, antagomiR-218 reached 40-60 pM 2weeks after injection, rescued molecular and functional phenotypes in a dose- and time-dependent manner, and showed a good toxicity profile after a single subcutaneous administration. In muscle tissue, antagomiR rescued the normal subcellular distribution of Mbnl1 and did not alter the proportion of myonuclei containing CUG foci. In patient-derived cells, antagomiR-218 improved defective fusion and differentiation and rescued up to 34% of the gene expression alterations found in the transcriptome of patient cells. Importantly, miR-218 was found to be upregulated in DM1 muscle biopsies, pinpointing this microRNA (miRNA) as a relevant therapeutic target.es_ES
dc.description.sponsorshipThis work was funded by research grants from Instituto de Salud Carlos III, including funds from FEDER, to M.P.-A. and B.L. (PI17/00352) and HR17-00268 (TATAMI project) from the “la Caixa” Banking Foundation to R.A. I.G.-M. was funded by the Precipita Project titled “Desarrollo de una terapia innovadora contra la distrofia miotónica,” E.C.-H. and J.M.F.-C. were supported by the post-doctoral fellowships APOSTD/2019/142 and APOSTD/2017/088 from the Fondo Social Europeo for science and investigation, while J.E.-E. was the recipient of a Santiago Grisolia fellowship (Grisolip2018/098) from the Generalidad Valenciana. Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020). Antibody MB1a (4A8) was provided by MDA Monoclonal Antibody Resourceses_ES
dc.language.isoenges_ES
dc.publisherElsevieres_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/*
dc.subjectCTG repeat expansionses_ES
dc.subjectMBNL1 proteines_ES
dc.subjectalternative splicinges_ES
dc.subjectantisense oligonucleotidees_ES
dc.subjectmicroRNAses_ES
dc.subjectmyotonic dystrophyes_ES
dc.subjecttherapeutic gene modulationes_ES
dc.subjecttissue distributiones_ES
dc.subjecttranscriptomicses_ES
dc.titlePreclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophyes_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.holderThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 4.0)es_ES
dc.rights.holderAtribución-NoComercial-SinDerivadas 3.0 España*
dc.relation.publisherversionhttps://www-sciencedirect-com.ehu.idm.oclc.org/science/article/pii/S2162253121001852?via%3Dihub#!es_ES
dc.identifier.doi10.1016/j.omtn.2021.07.017
dc.departamentoesNeurocienciases_ES
dc.departamentoeuNeurozientziakes_ES


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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 4.0)
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