摘要
肌强直性营养不良(DM)是成人中最常见的一种神经肌肉疾病,由两个遗传学上截然不同的形式组成,所引发在非编码区域不稳定重复扩大。最常见的DM1由DMPK基因3''UTR扩增的CTG重复序列引起,而DM2是由CNBP基因第一内含子大量扩增的CCTG重复序列引起。两种基因突变引起一种致病RNA增效作用机制。突变的RNA包括 CUG或CCUG扩增重复序列被保留在细胞核中,作为聚集体改变剪接调节者如MBNL蛋白质和celf1的活动。因此,一些前体mRNA选择性剪接的错误调节与糖尿病临床症状相关。目前,这种神经肌肉疾病没有有效的治疗方法。然而,在过去的十年中已经开发了很有前途的治疗手段。DM临床前研究进展促进DM1第一临床试验,这些试验需在反义寡核苷酸促进扩展CUG转录的RNA酶H-介导的降解基础上进行。1/2a临床试验的持续阶段将有望为DM1寻求一个真正的治愈方案。本文将对中和DM1中RNA毒性的不同方法进行逐一概述,如反义寡核苷酸技术,基因治疗或小分子疗法,且已在细胞和动物模型中进行了测试和验证。此外,面临的挑战和更多的方法也将在此逐一进行探讨。
关键词: 肌强直性营养不良,DM1,DM2,DMPK,CNBP,CTG重复序列,CCTG重复序列,MBNL,基因治疗,反义寡核苷酸
Current Gene Therapy
Title:Therapeutic Approaches for Dominant Muscle Diseases: Highlight on Myotonic Dystrophy
Volume: 15 Issue: 4
Author(s): A. F. Klein, S. Dastidar, D. Furling and M. K. Chuah
Affiliation:
关键词: 肌强直性营养不良,DM1,DM2,DMPK,CNBP,CTG重复序列,CCTG重复序列,MBNL,基因治疗,反义寡核苷酸
摘要: Myotonic Dystrophy (DM), one of the most common neuromuscular disorders in adults, comprises two genetically distinct forms triggered by unstable expanded repeats in non-coding regions. The most common DM1 is caused by expanded CTG repeats in the 3’UTR of the DMPK gene, whereas DM2 is due to large expanded CCTG repeats in the first intron of the CNBP gene. Both mutations induce a pathogenic RNA gain-of-function mechanism. Mutant RNAs containing CUG or CCUG expanded repeats, which are retained in the nuclei as aggregates alter activities of alternative splicing regulators such as MBNL proteins and CELF1. As a consequence, alternative splicing misregulations of several pre-mRNAs are associated with DM clinical symptoms. Currently, there is no available cure for this dominant neuromuscular disease. Nevertheless, promising therapeutic strategies have been developed in the last decade. Preclinical progress in DM research prompted the first DM1 clinical trial based on antisense oligonucleotides promoting a RNase-H-mediated degradation of the expanded CUG transcripts. The ongoing Phase 1/2a clinical trial will hopefully give further insights into the quest to find a bona fide cure for DM1. In this review, we will provide an overview of the different strategies that were developed to neutralize the RNA toxicity in DM1. Different approaches including antisense oligonucleotide technologies, gene therapies or small molecules have been tested and validated in cellular and animal models. Remaining challenges and additional avenues to explore will be discussed.
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Cite this article as:
A. F. Klein, S. Dastidar, D. Furling and M. K. Chuah , Therapeutic Approaches for Dominant Muscle Diseases: Highlight on Myotonic Dystrophy, Current Gene Therapy 2015; 15 (4) . https://dx.doi.org/10.2174/1566523215666150630120537
DOI https://dx.doi.org/10.2174/1566523215666150630120537 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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