小柯机器人

美国Wave生命科学公司Chandra Vargeese团队发现，新方法可在非人类灵长类动物中进行内源性ADAR介导的RNA编辑。该研究于2022年3月7日在线发表于国际一流学术期刊《自然—生物技术》。

研究人员描述了被称为AIMers的短的化学修饰寡核苷酸，它能引导作用于RNA的内源性腺苷脱氨酶（ADAR）酶对内源性转录本进行高效和特异的A-I编辑，包括普遍和组成性表达的ADAR1 p110异构体。结果表明，与体外具有统一硫代磷酸酯修饰骨架的AIMers相比，具有含有stereopure硫代磷酸酯和基于磷酰胍的含氮连接嵌合骨架全化学修饰AIMers的效力和编辑效率提高了100倍。

在体内，以N-乙酰半乳糖胺为靶点的AIMers在非人灵长类动物的肝脏中实现了高达50%的编辑，并且没有对内源性ACTB转录本进行旁观者编辑，编辑至少持续一个月。这些结果支持对AIMers的治疗潜力进行进一步调查。

据介绍，招募内源性RNA编辑酶并将其活性导向特定RNA的技术具有治疗潜力，但将其从细胞培养转化到动物模型一直是个挑战。

附：英文原文

Title: Endogenous ADAR-mediated RNA editing in non-human primates using stereopure chemically modified oligonucleotides

Author: Monian, Prashant, Shivalila, Chikdu, Lu, Genliang, Shimizu, Mamoru, Boulay, David, Bussow, Karley, Byrne, Michael, Bezigian, Adam, Chatterjee, Arindom, Chew, David, Desai, Jigar, Favaloro, Frank, Godfrey, Jack, Hoss, Andrew, Iwamoto, Naoki, Kawamoto, Tomomi, Kumarasamy, Jayakanthan, Lamattina, Anthony, Lindsey, Amber, Liu, Fangjun, Looby, Richard, Marappan, Subramanian, Metterville, Jake, Murphy, Ronelle, Rossi, Jeff, Pu, Tom, Bhattarai, Bijay, Standley, Stephany, Tripathi, Snehlata, Yang, Hailin, Yin, Yuan, Yu, Hui, Zhou, Cong, Apponi, Luciano H., Kandasamy, Pachamuthu, Vargeese, Chandra

Issue&Volume: 2022-03-07

Abstract: Technologies that recruit and direct the activity of endogenous RNA-editing enzymes to specific cellular RNAs have therapeutic potential, but translating them from cell culture into animal models has been challenging. Here we describe short, chemically modified oligonucleotides called AIMers that direct efficient and specific A-to-I editing of endogenous transcripts by endogenous adenosine deaminases acting on RNA (ADAR) enzymes, including the ubiquitously and constitutively expressed ADAR1 p110 isoform. We show that fully chemically modified AIMers with chimeric backbones containing stereopure phosphorothioate and nitrogen-containing linkages based on phosphoryl guanidine enhanced potency and editing efficiency 100-fold compared with those with uniformly phosphorothioate-modified backbones in vitro. In vivo, AIMers targeted to hepatocytes with N-acetylgalactosamine achieve up to 50% editing with no bystander editing of the endogenous ACTB transcript in non-human primate liver, with editing persisting for at least one month. These results support further investigation of the therapeutic potential of stereopure AIMers. RNA in non-human primate liver is efficiently edited using short stereopure oligonucleotides.

DOI: 10.1038/s41587-022-01225-1

Source: https://www.nature.com/articles/s41587-022-01225-1

Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
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