Stereopure oligo therapy for ALS.
Stereopure oligo therapy for ALS.
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用于 ALS 的 Stereopure 寡核苷酸疗法。
DOI：
10.1016/j.ymthe.2022.04.026
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Rossi,JohnJ
中科院分区：
文献类型：
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作者：
Rossi,JohnJ
第一个被批准用于临床的针对巨细胞病毒(CMV)的反义寡核苷酸(ASO)被设计用于治疗CMV视网膜炎。尽管这一患者市场有限，但它还是引发了人们对这项技术的兴趣增加。尽管它们具有多功能性，但硫代磷酸反义寡核苷酸在每个核苷酸上都具有手性，导致与其RNA互补的杂交不太稳定。因此，20-聚体以数十万种不同活性的手性形式存在，包括与其目标杂交的能力。这个问题使得针对与野生型等位基因版本相比碱基变化较小的疾病信使RNA变得困难。波浪生命科学已经解决了手性问题，最近开发了含有磷酰胍(PN)主链的立体ASO。最近发表在分子治疗核酸1上的一篇文章在临床前环境中测试了这种化学，他们证明了他们针对六核苷酸重复(WVE-004)的立体视觉ASO选择性地触发了肌萎缩侧索硬化症(ALS)患者衍生的运动神经元和ALS转基因小鼠模型中含有重复序列的转录本的降解。第一次证明ASO可以在细胞培养中抑制呼吸道合胞病毒(RSV)复制是在50多年前。2随着DNA寡核苷酸快速合成方法的出现，反义治疗领域开始腾飞。大多数早期的申请都是
The first antisense oligonucleotide (ASO) approved for clinical use targeted cytomegalovirus (CMV) and was designed to treat CMV retinitis. Although this patient market is limited, it nevertheless triggered increased interest in the technology. Despite their versatility, phosphorothioate ASOs possess chirality at each nucleotide, resulting in less stable hybrids with their RNA complement. Thus, a 20-mer exists as hundreds of thousands of chiral forms that differ in activity, including the ability to hybridize to their target. This problem makes it difficult to specifically target disease messenger RNAs that have small base change mutations relative to the wild-type allelic version. Wave Life Sciences has tackled the problem of chirality with the recent development of stereopure ASOs with phosphoryl guanidine (PN)-containing backbone linkages. A recent publication in Molecular Therapy Nucleic Acids 1 tests this chemistry in a preclinical setting whereby they demonstrate that their stereopure ASO targeting the hexanucleotide repeat (WVE-004) selectively triggers degradation of repeat-containing transcripts both in amyotrophic lateral sclerosis (ALS) patient-derived motor neurons and in a transgenic mouse model of ALS.The first demonstration that an ASO could inhibit respiratory syncytial virus (RSV) replication in cell culture took place over 50 years ago. 2 With the advent of rapid DNA oligonucleotide synthesis methods, the field of antisense therapeutics took off. Most of the early applications were