Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer's disease
Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer's disease
复制标题
将小干扰 RNA 递送至淀粉样斑块附近的神经元，以改善阿尔茨海默病的治疗
DOI：
10.1016/j.apsb.2018.12.010
复制
发表时间：
2019-05-01
影响因子：
14.5
通讯作者：
Jiang, Xinguo
中科院分区：
文献类型：
--
作者：
Guo, Qian;Zheng, Xiaoyao;Jiang, Xinguo
基因治疗是治疗阿尔茨海默病（AD）的一种有效方法。然而，通过全身给药将特异性基因递送到脑病变仍然是一个巨大的挑战。在我们之前的工作中，我们已经开发了一种siRNA纳米复合物，该复合物能够通过用CGN肽进行表面修饰而特异性地递送至淀粉样蛋白斑块，CGN肽用于血脑屏障（BBB）渗透，QSH肽用于J3-淀粉样蛋白结合。但是，所设计的纳米复合物是否真的可以改善受损神经元细胞中的基因积累并改善AD相关症状仍有待进一步研究。在本文中，我们制备了具有针对β-位点淀粉样前体蛋白裂解酶1（BACE 1）的siRNA的纳米复合物，作为AD的治疗性siRNA，β-位点淀粉样前体蛋白裂解酶1（BACE 1）是A β产生的限速酶。纳米复合物在富含A/3沉积物的海马中表现出较高的分布，特别是在静脉给药后淀粉样斑块附近的神经元中。在APP/PS1转基因小鼠中，纳米复合物在mRNA和蛋白质水平以及A/3和淀粉样蛋白斑块中下调BACE 1至野生型小鼠的水平。此外，纳米复合物显着增加突触素的水平，挽救AD转基因小鼠的记忆丧失，而没有血液学或组织学毒性。总之，这项工作提供了直接的证据，精确的基因递送到AD病变的设计显着改善治疗结果。(C)2019中国药学会、中国医学科学院药物研究所。制作和主办：Elsevier B. V.
Gene therapy represents a promising treatment for the Alzheimer's disease (AD). However, gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have developed an siRNA nanocomplex able to be specifically delivered to the amyloid plaques through surface modification with both CGN peptide for the blood brain bather (BBB) penetration and QSH peptide for J3-amyloid binding. But, whether the as-designed nanocomplex could indeed improve the gene accumulation in the impaired neuron cells and ameliorate AD-associated symptoms remains further study. Herein, we prepared the nanocomplexes with an siRNA against /3-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of A/3 production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the A/3 deposits-enriched hippocampus, especially in the neurons near the amyloid plaques after intravenous administration. In APP/PS1 transgenic mice, the nanocomplexes down-regulated BACE1 in both mRNA and protein levels, as well as A/3 and amyloid plaques to the level of wild-type mice. Moreover, the nanocomplexes significantly increased the level of synaptophysin and rescued memory loss of the AD transgenic mice without hematological or histological toxicity. Taken together, this work presented direct evidences that the design of precise gene delivery to the AD lesions markedly improves the therapeutic outcome. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.