4.2抗病毒治疗

　　由于RNAi是机体中古老而天然的抗病毒机制,HIV病毒感染是我们亟待解决的问题,将RNAi技术应用于艾滋病治疗是顺理成章之事.目前利用RNAi抗病毒感染的研究已经展开,主要集中在HIV病毒和脊髓灰质炎病毒,并取得了令人鼓舞的结果[12].针对HIV病毒研究有Jacque等[13]设计的抑制HIV21长末端重复序列、附件基因vif和nef表达的siRNA,Lee等[14]针对rev转录子设计的siRNA及Novina等[15]针对HIV病毒gag基因设计的siRNA,其基本策略都是选择HIV病毒或宿主细胞基因为靶点.然而,RNAi治疗HIV,应用于临床,有几个重要问题必须解决[16].a)作用靶点的选择.siRNA对序列要求非常严格,1个碱基的错配,将大大降低siRNA基因表达抑制作用.如果HIV逆转录酶有较高的错配率(1/1000个核苷酸每个复制循环),就可能迅速导致所谓siRNA逃逸突变的出现.感染个体中HIV序列的多样性,为siRNA的设计和合成增加了难度.B)如何有效导入siRNA.DNA质粒、逆转录病毒载体、腺病毒载体和脂质体等在培养细胞株中有良好的导入效果,但在原代细胞中效果较差.C)增强siRNA在细胞中的稳定性.为了防止细胞内RNA酶对siRNA的降解,可以用DNA质粒和病毒载体将siRNA以发夹(hairpins)的形式导入细胞内.

　　4.3抗肿瘤治疗

　　多种癌基因可以作为靶点设计相对应的siRNA[17].Brummelkamp等[18]用逆转录病毒载体将siRNA导入肿瘤细胞中,特异性抑制了癌基因K-RAS(V12)的表达.对急性髓性白血病的研究已经取得了乐观的结果.Scherr等[19]以引起慢性髓性白血病和bcr2abl阳性急性成淋巴细胞白血病的bcr2abl癌基因为靶基因,设计了对应的siRNA,并获得了87%的有效抑制率.Wilda等[20]用siRNA抑制白血病BCR/ABL融合基因表达也取得了成功.因此基于RNAi技术的抗肿瘤治疗药物开发潜力巨大.

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