Estefanía Cerro-Herreros, Judit Núñez-Manchón, Neia Naldaiz-Gastesi, Marc Carrascosa-Sàez, Andrea García-Rey, Diego Piqueras Losilla, Irene González-Martínez, Jorge Espinosa-Espinosa, Kevin Moreno, Javier Poyatos-García, Juan J Vilchez, Adolfo López de Munain, Mònica Suelves, Gisela Nogales-Gadea, Beatriz Llamusí, Rubén Artero
{"title":"AntimiR疗法通过双重作用机制纠正了多个CTG重复扩展的肌营养不良症原代细胞缺陷。","authors":"Estefanía Cerro-Herreros, Judit Núñez-Manchón, Neia Naldaiz-Gastesi, Marc Carrascosa-Sàez, Andrea García-Rey, Diego Piqueras Losilla, Irene González-Martínez, Jorge Espinosa-Espinosa, Kevin Moreno, Javier Poyatos-García, Juan J Vilchez, Adolfo López de Munain, Mònica Suelves, Gisela Nogales-Gadea, Beatriz Llamusí, Rubén Artero","doi":"10.1126/sciadv.adn6525","DOIUrl":null,"url":null,"abstract":"<p><p>This study evaluated therapeutic antimiRs in primary myoblasts from patients with myotonic dystrophy type 1 (DM1). DM1 results from unstable CTG repeat expansions in the <i>DMPK</i> gene, leading to variable clinical manifestations by depleting muscleblind-like splicing regulator protein MBNL1. AntimiRs targeting natural repressors miR-23b and miR-218 boost MBNL1 expression but must be optimized for a better pharmacological profile in humans. In untreated cells, miR-23b and miR-218 were up-regulated, which correlated with CTG repeat size, supporting that active MBNL1 protein repression synergizes with the sequestration by CUG expansions in <i>DMPK</i>. AntimiR treatment improved RNA toxicity readouts and corrected regulated exon inclusions and myoblast defects such as fusion index and myotube area across CTG expansions. Unexpectedly, the treatment also reduced <i>DMPK</i> transcripts and ribonuclear foci. A leading antimiR reversed 68% of dysregulated genes. This study highlights the potential of antimiRs to treat various DM1 forms across a range of repeat sizes and genetic backgrounds by mitigating MBNL1 sequestration and enhancing protein synthesis.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7000,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463307/pdf/","citationCount":"0","resultStr":"{\"title\":\"AntimiR treatment corrects myotonic dystrophy primary cell defects across several CTG repeat expansions with a dual mechanism of action.\",\"authors\":\"Estefanía Cerro-Herreros, Judit Núñez-Manchón, Neia Naldaiz-Gastesi, Marc Carrascosa-Sàez, Andrea García-Rey, Diego Piqueras Losilla, Irene González-Martínez, Jorge Espinosa-Espinosa, Kevin Moreno, Javier Poyatos-García, Juan J Vilchez, Adolfo López de Munain, Mònica Suelves, Gisela Nogales-Gadea, Beatriz Llamusí, Rubén Artero\",\"doi\":\"10.1126/sciadv.adn6525\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>This study evaluated therapeutic antimiRs in primary myoblasts from patients with myotonic dystrophy type 1 (DM1). DM1 results from unstable CTG repeat expansions in the <i>DMPK</i> gene, leading to variable clinical manifestations by depleting muscleblind-like splicing regulator protein MBNL1. AntimiRs targeting natural repressors miR-23b and miR-218 boost MBNL1 expression but must be optimized for a better pharmacological profile in humans. In untreated cells, miR-23b and miR-218 were up-regulated, which correlated with CTG repeat size, supporting that active MBNL1 protein repression synergizes with the sequestration by CUG expansions in <i>DMPK</i>. AntimiR treatment improved RNA toxicity readouts and corrected regulated exon inclusions and myoblast defects such as fusion index and myotube area across CTG expansions. Unexpectedly, the treatment also reduced <i>DMPK</i> transcripts and ribonuclear foci. A leading antimiR reversed 68% of dysregulated genes. This study highlights the potential of antimiRs to treat various DM1 forms across a range of repeat sizes and genetic backgrounds by mitigating MBNL1 sequestration and enhancing protein synthesis.</p>\",\"PeriodicalId\":21609,\"journal\":{\"name\":\"Science Advances\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":11.7000,\"publicationDate\":\"2024-10-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463307/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Advances\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1126/sciadv.adn6525\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/9 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Advances","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1126/sciadv.adn6525","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/9 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
AntimiR treatment corrects myotonic dystrophy primary cell defects across several CTG repeat expansions with a dual mechanism of action.
This study evaluated therapeutic antimiRs in primary myoblasts from patients with myotonic dystrophy type 1 (DM1). DM1 results from unstable CTG repeat expansions in the DMPK gene, leading to variable clinical manifestations by depleting muscleblind-like splicing regulator protein MBNL1. AntimiRs targeting natural repressors miR-23b and miR-218 boost MBNL1 expression but must be optimized for a better pharmacological profile in humans. In untreated cells, miR-23b and miR-218 were up-regulated, which correlated with CTG repeat size, supporting that active MBNL1 protein repression synergizes with the sequestration by CUG expansions in DMPK. AntimiR treatment improved RNA toxicity readouts and corrected regulated exon inclusions and myoblast defects such as fusion index and myotube area across CTG expansions. Unexpectedly, the treatment also reduced DMPK transcripts and ribonuclear foci. A leading antimiR reversed 68% of dysregulated genes. This study highlights the potential of antimiRs to treat various DM1 forms across a range of repeat sizes and genetic backgrounds by mitigating MBNL1 sequestration and enhancing protein synthesis.
期刊介绍:
Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.