Increase in Full-Length Dystrophin by Exon Skipping in Duchenne Muscular Dystrophy Patients with Single Exon Duplications: An Open-label Study.

IF 3.2 4区医学 Q2 CLINICAL NEUROLOGY

Journal of neuromuscular diseases Pub Date : 2024-01-01 DOI:10.3233/JND-230107

Stefan Nicolau, Jyoti Malhotra, Maryann Kaler, Pamela Magistrado-Coxen, Megan A Iammarino, Natalie F Reash, Emma C Frair, Saranga Wijeratne, Benjamin J Kelly, Peter White, Linda P Lowes, Megan A Waldrop, Kevin M Flanigan

{"title":"Increase in Full-Length Dystrophin by Exon Skipping in Duchenne Muscular Dystrophy Patients with Single Exon Duplications: An Open-label Study.","authors":"Stefan Nicolau, Jyoti Malhotra, Maryann Kaler, Pamela Magistrado-Coxen, Megan A Iammarino, Natalie F Reash, Emma C Frair, Saranga Wijeratne, Benjamin J Kelly, Peter White, Linda P Lowes, Megan A Waldrop, Kevin M Flanigan","doi":"10.3233/JND-230107","DOIUrl":null,"url":null,"abstract":"<p><p>Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"679-685"},"PeriodicalIF":3.2000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091625/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of neuromuscular diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3233/JND-230107","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications.

查看原文本刊更多论文

单外显子重复的杜兴氏肌肉萎缩症患者通过外显子缺失增加全长肌营养不良蛋白：一项开放标签研究

单外显子重复是少数杜氏肌营养不良症患者患病的原因。通过恢复全长肌营养不良蛋白的表达，这些患者的外显子跳越具有很强的治疗潜力。我们对3名患有外显子45或53重复的受试者进行了为期48周的卡西美森和戈洛迪森开放标签研究。两名受试者（年龄分别为 18 岁和 23 岁）基线时不能行走。在可以进行评估的两名受试者中，上肢、肺部和心脏功能似乎都很稳定。通过 Western 印迹，肌营养不良蛋白的表达从正常值的 0.94% ±0.59%（平均值±SD）增加到 5.1% ±2.9%。肌营养不良蛋白阳性纤维的百分比也从基线时的 14% ±17% 上升到 50% ±42% 。我们的研究结果提供了初步证据，证明使用外显子切割药物可提高单外显子重复患者的肌营养不良素水平。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of neuromuscular diseases Medicine-Neurology (clinical)

CiteScore

5.10

自引率

6.10%

发文量

102

期刊介绍： The Journal of Neuromuscular Diseases aims to facilitate progress in understanding the molecular genetics/correlates, pathogenesis, pharmacology, diagnosis and treatment of acquired and genetic neuromuscular diseases (including muscular dystrophy, myasthenia gravis, spinal muscular atrophy, neuropathies, myopathies, myotonias and myositis). The journal publishes research reports, reviews, short communications, letters-to-the-editor, and will consider research that has negative findings. The journal is dedicated to providing an open forum for original research in basic science, translational and clinical research that will improve our fundamental understanding and lead to effective treatments of neuromuscular diseases.