Bauman John, Jearawiriyapaisarn Natee, Kole Ryszard
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA.
Oligonucleotides. 2009 Mar;19(1):1-13. doi: 10.1089/oli.2008.0161.
Alternative splicing enables a single pre-messenger RNA transcript to yield multiple protein isoforms, making it a major contributor to the diversity of the proteome. While this process is essential for normal development, aberrations in alternative splicing are the cause of a multitude of human diseases. Methods for manipulating alternative splicing would thus be of therapeutic value. Chemically modified antisense oligonucleotides that alter alternative splicing by directing splice site selection have been developed to achieve this end. These splice-switching oligonucleotides (SSOs) have been applied to correct aberrant splicing, induce expression of a therapeutic splice variant, or induce expression of a novel therapeutic splice variant in a number of disease-relevant genes. Recently, in vivo efficacy of SSOs has been reported using animal disease models, as well as in results from the first clinical trial.
可变剪接使单个信使前体RNA转录本产生多种蛋白质异构体，使其成为蛋白质组多样性的主要贡献因素。虽然这一过程对正常发育至关重要，但可变剪接异常是多种人类疾病的病因。因此，操纵可变剪接的方法具有治疗价值。为实现这一目的，已开发出通过指导剪接位点选择来改变可变剪接的化学修饰反义寡核苷酸。这些剪接转换寡核苷酸（SSO）已被应用于纠正异常剪接、诱导治疗性剪接变体的表达，或在一些与疾病相关的基因中诱导新型治疗性剪接变体的表达。最近，已报道了使用动物疾病模型的SSO体内疗效以及首个临床试验的结果。
