Transvascular delivery of small interfering RNA to the central nervous system
Transvascular delivery of small interfering RNA to the central nervous system
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DOI：
10.1038/nature05901
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发表时间：
2007-07-05
期刊：
影响因子：
64.8
通讯作者：
Manjunath, N.
中科院分区：
文献类型：
--
作者：
Kumar, Priti;Wu, Haoquan;Manjunath, N.
治疗神经系统疾病的主要障碍是血脑屏障的存在，其阻止治疗分子从血液进入脑。在这里，我们表明，来自狂犬病病毒糖蛋白（RVG）的短肽，使小干扰RNA（siRNA）的经血管输送到大脑。这种29个氨基酸的肽特异性结合神经元细胞表达的乙酰胆碱受体。为了使siRNA能够结合，通过在RVG的羧基末端添加九聚体精氨酸残基来合成嵌合肽。该RVG-9 R肽能够在体外结合并阻断siRNA至神经元细胞，从而导致有效的基因沉默。在静脉注射到小鼠体内后，RVG-9 R将siRNA递送到神经元细胞，导致大脑内的特定基因沉默。此外，用RVG-9 R结合的抗病毒siRNA静脉内治疗在小鼠中提供了针对致命病毒性脑炎的强有力的保护。重复给予RVG-9 R结合的SiRNA不会诱导炎症细胞因子或抗肽抗体。因此，RVG-9 R提供了一种用于递送siRNA和潜在的其他治疗分子穿过血脑屏障的安全且非侵入性的方法。
A major impediment in the treatment of neurological diseases is the presence of the blood - brain barrier, which precludes the entry of therapeutic molecules from blood to brain. Here we show that a short peptide derived from rabies virus glycoprotein (RVG) enables the transvascular delivery of small interfering RNA ( siRNA) to the brain. This 29-amino-acid peptide specifically binds to the acetylcholine receptor expressed by neuronal cells. To enable siRNA binding, a chimaeric peptide was synthesized by adding nonamer arginine residues at the carboxy terminus of RVG. This RVG-9R peptide was able to bind and transduce siRNA to neuronal cells in vitro, resulting in efficient gene silencing. After intravenous injection into mice, RVG-9R delivered siRNA to the neuronal cells, resulting in specific gene silencing within the brain. Furthermore, intravenous treatment with RVG-9R-bound antiviral siRNA afforded robust protection against fatal viral encephalitis in mice. Repeated administration of RVG-9R-bound siRNA did not induce inflammatory cytokines or anti-peptide antibodies. Thus, RVG-9R provides a safe and noninvasive approach for the delivery of siRNA and potentially other therapeutic molecules across the blood - brain barrier.