小柯机器人

日本东京医科齿科大学Takanori Yokota团队发现，胆固醇功能化的DNA/RNA异源双链体可穿过血脑屏障，并敲低啮齿动物中枢神经系统（CNS）中的基因 。相关论文于2021年8月12日在线发表在《自然—生物技术》杂志上。

研究人员证明，在小鼠和大鼠皮下或静脉内给药后，在RNA链5'端与胆固醇或α-生育酚结合的DNA/RNA异源双链寡核苷酸（HDO）能够到达CNS。HDO分布在整个大脑、脊髓和外周组织中，并在CNS中抑制四种靶基因的表达高达90%，而与胆固醇结合的单链反义寡核苷酸（ASO）活性有限。研究人员在主要的CNS类型中观察到基因敲低，且在神经元和小胶质细胞中最为明显。

副作用（如血小板减少症和局灶性脑坏死）可通过皮下给药或分开静脉注射来降低。通过更有效地穿越血脑屏障，胆固醇结合的HDO可以克服ASO靶向CNS的功效，而无需鞘内给药。

据介绍，通过全身施用ASO实现对CNS内源性基因表达的调节将促进ASO神经系统疾病疗法的发展。

附：英文原文

Title: Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood–brain barrier and knock down genes in the rodent CNS

Author: Nagata, Tetsuya, Dwyer, Chrissa A., Yoshida-Tanaka, Kie, Ihara, Kensuke, Ohyagi, Masaki, Kaburagi, Hidetoshi, Miyata, Haruka, Ebihara, Satoe, Yoshioka, Kotaro, Ishii, Takashi, Miyata, Kanjiro, Miyata, Kenichi, Powers, Berit, Igari, Tomoko, Yamamoto, Syunsuke, Arimura, Naoto, Hirabayashi, Hideki, Uchihara, Toshiki, Hara, Rintaro Iwata, Wada, Takeshi, Bennett, C. Frank, Seth, Punit P., Rigo, Frank, Yokota, Takanori

Issue&Volume: 2021-08-12

Abstract: Achieving regulation of endogenous gene expression in the central nervous system (CNS) with antisense oligonucleotides (ASOs) administered systemically would facilitate the development of ASO-based therapies for neurological diseases. We demonstrate that DNA/RNA heteroduplex oligonucleotides (HDOs) conjugated to cholesterol or α-tocopherol at the 5′ end of the RNA strand reach the CNS after subcutaneous or intravenous administration in mice and rats. The HDOs distribute throughout the brain, spinal cord and peripheral tissues and suppress the expression of four target genes by up to 90% in the CNS, whereas single-stranded ASOs conjugated to cholesterol have limited activity. Gene knockdown was observed in major CNS cell types and was greatest in neurons and microglial cells. Side effects, such as thrombocytopenia and focal brain necrosis, were limited by using subcutaneous delivery or by dividing intravenous injections. By crossing the blood–brain barrier more effectively, cholesterol-conjugated HDOs may overcome the limited efficacy of ASOs targeting the CNS without requiring intrathecal administration.

DOI: 10.1038/s41587-021-00972-x

Source: https://www.nature.com/articles/s41587-021-00972-x

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
官方网址：https://www.nature.com/nbt/
投稿链接：https://mts-nbt.nature.com/cgi-bin/main.plex