Nature:RNAi的新里程碑

【字体: www.ebiotrade.com 时间:2009年05月04日 来源:Nature

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  生物通报道,马萨诸塞州大学医学院分子医学系Michael P. Czech和Gary R. Ostroff 的RNAi文章Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation发表在最新一期的Nature杂志发表RNAi的研究新成果,这一成果将成为RNAi领域的里程碑式成果。

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生物通报道,马萨诸塞州大学医学院分子医学系Michael P. CzechGary R. Ostroff RNAi文章Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation发表在最新一期的Nature杂志发表这一成果将成为RNAi领域的里程碑式成果。

 

RNA干扰是目前生命科学领域中的前沿技术,从发现至今,科学家们都将治愈疑难疾病的希望寄托在能阻断基因表达的RNAi技术上,无疑,RNAi具有巨大的治疗潜力。然而,RNAi的传递系统一直是科学家们头疼的问题。要使RNAi技术安全有效,必须克服重重障碍。

 

今天,输送siRNA的新方式诞生了,这一技术为RNAi技术开拓了全新的视野。Michael P. CzechGary R. Ostroff等设计一种新的传递系统,将siRNA装在微米尺度的β,3-D葡聚糖中,这一siRNA针对巨噬细胞中的MAP4k4酶(一种介导细胞因子表达的酶),研究人员将这一葡聚糖颗粒以口服的形式给疾病模型小鼠(患有脂多糖诱导的炎症疾病)。结果发现接受了葡聚糖-siRNA颗粒治疗的小鼠存活率提高了,葡聚糖携带的siRNA能有效抑制全身性炎症。

 

研究人员将这种方法与传统的siRNA传递系统对比发现,新的口服形式的传递系统比传统的传递系统的效率高250倍。这一技术为科学家们研发其他类别的口服RNAi药物提供了思路。

 

(生物通 小茜)

 

生物通推荐原文检索:Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation

Abstract

Gene silencing by double-stranded RNA, denoted RNA interference, represents a new paradigm for rational drug design1. However, the transformative therapeutic potential of short interfering RNA (siRNA) has been stymied by a key obstaclesafe delivery to specified target cells in vivo 2. Macrophages are particularly attractive targets for RNA interference therapy because they promote pathogenic inflammatory responses in diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and diabetes3. Here we report the engineering of 1,3-d-glucan-encapsulated siRNA particles (GeRPs) as efficient oral delivery vehicles that potently silence genes in mouse macrophages in vitro and in vivo. Oral gavage of mice with GeRPs containing as little as 20 g kg-1 siRNA directed against tumour necrosis factor  (Tnf-) depleted its messenger RNA in macrophages recovered from the peritoneum, spleen, liver and lung, and lowered serum Tnf- levels. Screening with GeRPs for inflammation genes revealed that the mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) is a previously unknown mediator of cytokine expression. Importantly, silencing Map4k4 in macrophages in vivo protected mice from lipopolysaccharide-induced lethality by inhibiting Tnf- and interleukin-1 production. This technology defines a new strategy for oral delivery of siRNA to attenuate inflammatory responses in human disease.

 

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