美国麻省医学院Anastasia Khvorova团队提出了一种二价siRNA化学构架，在整个中枢神经系统中对基因表达进行有效和持续的调控。 相关论文于2019年8月发表于国际顶尖学术期刊《自然—生物技术》上。

本项研究中，小组描述一个新的siRNA结构：二阶siRNA(di-siRNA)。该结构有力地支持其在小鼠和非人灵长类动物的枢神经系统(CNS)内实现基因的可保持沉默，其过程只需要一次脑脊液内的注射。Di-siRNAs是由两个完全化学改性的，含硫代磷酸的siRNAs连接而成。在小鼠体内，di-siRNAs诱导亨廷顿蛋白（亨廷顿舞蹈病的致病基因）的强力沉默，,减少了整个脑部的信使RNA和蛋白质。沉默持续至少6个月，基因沉默的程度与引导链在组织内的积聚水平相关。研究者在食蟹猴内注射di-siRNA一次后，在整个大脑和脊髓中显示出分布广泛地强力沉默，没有检测到毒性，并且具有最小的脱靶效应。这种siRNA设计，可能使得基于RNA干扰的基因沉默在中枢神经系统内用于神经系统疾病的治疗。

据了解，目前，人们还无法利用小干扰RNA（siRNA）实现整个脑部基因的可保持沉默。

附：英文原文

Title: A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system

Author: Julia F. Alterman, Bruno M. D. C. Godinho, Matthew R. Hassler, Chantal M. Ferguson, Dimas Echeverria, Ellen Sapp, Reka A. Haraszti, Andrew H. Coles, Faith Conroy, Rachael Miller, Loic Roux, Paul Yan, Emily G. Knox, Anton A. Turanov, Robert M. King, Gwladys Gernoux, Christian Mueller, Heather L. Gray-Edwards, Richard P. Moser, Nina C. Bishop, Samer M. Jaber, Matthew J. Gounis, Miguel Sena-Esteves, Athma A. Pai, Marian DiFiglia, Neil Aronin, Anastasia Khvorova

Issue&Volume: Volume 37，Issue8

Abstract: Sustained silencing of gene expression throughout the brain using small interfering RNAs (siRNAs) has not been achieved. Here we describe an siRNA architecture, divalent siRNA (di-siRNA), that supports potent, sustained gene silencing in the central nervous system (CNS) of mice and nonhuman primates following a single injection into the cerebrospinal fluid. Di-siRNAs are composed of two fully chemically modified, phosphorothioate-containing siRNAs connected by a linker. In mice, di-siRNAs induced the potent silencing of huntingtin, the causative gene in Huntingtons disease, reducing messenger RNA and protein throughout the brain. Silencing persisted for at least 6 months, with the degree of gene silencing correlating to levels of guide strand tissue accumulation. In cynomolgus macaques, a bolus injection of di-siRNA showed substantial distribution and robust silencing throughout the brain and spinal cord without detectable toxicity and with minimal off-target effects. This siRNA design may enable RNA interference-based gene silencing in the CNS for the treatment of neurological disorders.

DOI: 10.1038/s41587-019-0205-0

Source:https://www.nature.com/articles/s41587-019-0205-0