RNA 剪接错误疾病的基因治疗。

Genetic therapies for RNA mis-splicing diseases.

机构信息

Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.

出版信息

Trends Genet. 2011 May;27(5):196-205. doi: 10.1016/j.tig.2011.02.004. Epub 2011 Apr 15.

DOI:10.1016/j.tig.2011.02.004

Abstract

RNA mis-splicing diseases account for up to 15% of all inherited diseases, ranging from neurological to myogenic and metabolic disorders. With greatly increased genomic sequencing being performed for individual patients, the number of known mutations affecting splicing has risen to 50-60% of all disease-causing mutations. During the past 10years, genetic therapy directed toward correction of RNA mis-splicing in disease has progressed from theoretical work in cultured cells to promising clinical trials. In this review, we discuss the use of antisense oligonucleotides to modify splicing as well as the principles and latest work in bifunctional RNA, trans-splicing and modification of U1 and U7 snRNA to target splice sites. The success of clinical trials for modifying splicing to treat Duchenne muscular dystrophy opens the door for the use of splicing modification for most of the mis-splicing diseases.

摘要

RNA 剪接错误疾病占所有遗传性疾病的 15%，包括神经肌肉和代谢紊乱。随着对个体患者进行的基因组测序大大增加，影响剪接的已知突变数量已上升到所有致病突变的 50-60%。在过去的 10 年中，针对疾病中 RNA 剪接错误的基因治疗已从培养细胞中的理论工作进展到有前途的临床试验。在这篇综述中，我们讨论了使用反义寡核苷酸来修饰剪接，以及双功能 RNA、反式剪接和修饰 U1 和 U7 snRNA 以靶向剪接位点的原理和最新进展。修饰剪接以治疗杜氏肌营养不良症的临床试验的成功为大多数剪接错误疾病的剪接修饰开辟了道路。