小柯机器人

美国国立卫生研究院Tom Misteli小组的最新研究通过系统筛选发现了可用于治疗小儿早老症（HGPS）的反义寡核苷酸。这一研究成果发表在2021年3月11日出版的国际学术期刊《自然-医学》上。

研究人员使用了体外筛选和体内验证相结合的方法，系统地研究了靶序列、骨架化学和作用机理以鉴定用于治疗HGPS的优化反义寡核苷酸（ASO）。在包涵198个ASO的库中，最有效的ASO靶向LMNA外显子12的连接，并通过非RNase H介导的机制起作用。在HGPS小鼠模型中，使用优化的潜在候选药物进行治疗可延长寿命。

重组Progerin mRNA水平在体内显著降低，但是组织间progerin蛋白的降低幅度有所不同，这表明progerin在体内的半衰期较长且存在组织特异性周转。这些结果揭示了一种新型的HGPS治疗剂，并为理解HGPS的发病机理提供了见识。

据了解，小儿早老症是由LMNA基因的前信使RNA（mRNA）剪接缺陷引起的罕见、致命性儿童过早衰老疾病。

附：英文原文

Title: Systematic screening identifies therapeutic antisense oligonucleotides for Hutchinson–Gilford progeria syndrome

Author: Madaiah Puttaraju, Michaela Jackson, Stephanie Klein, Asaf Shilo, C. Frank Bennett, Leslie Gordon, Frank Rigo, Tom Misteli

Issue&Volume: 2021-03-11

Abstract: Hutchinson–Gilford progeria syndrome (HGPS) is a rare, invariably fatal childhood premature aging disorder caused by a pre-messenger RNA (mRNA) splicing defect in the LMNA gene. We used combined in vitro screening and in vivo validation to systematically explore the effects of target sequence, backbone chemistry and mechanism of action to identify optimized antisense oligonucleotides (ASOs) for therapeutic use in HGPS. In a library of 198 ASOs, the most potent ASOs targeted the LMNA exon 12 junction and acted via non-RNase H-mediated mechanisms. Treatment with an optimized lead candidate resulted in extension of lifespan in a mouse model of HGPS. Progerin mRNA levels were robustly reduced in vivo, but the extent of progerin protein reduction differed between tissues, suggesting a long half-life and tissue-specific turnover of progerin in vivo. These results identify a novel therapeutic agent for HGPS and provide insight into the HGPS disease mechanism.

DOI: 10.1038/s41591-021-01262-4

Source: https://www.nature.com/articles/s41591-021-01262-4

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
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投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex