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Nature Medicine:miRNA改造病毒靶向治疗癌症
【字体: 大 中 小 】 时间:2008年10月29日 来源:Nature
编辑推荐:
生物通报道,来自梅奥临床研究中心的科学家近期使用microRNA对溶瘤病毒进行改造,使得溶瘤病毒成为靶向治疗的病毒载体,相关的成果发布在近期的Nature Medicine上。
研究者使用遗传手段在溶瘤病毒的3’端非编码区加入一段特异的microRNA序列,使得溶瘤病毒具有组织专嗜性。成为最佳的载体系统,可用于定向基因治疗载体或是药物治疗载体。
在该研究中,科学家将一段与肌肉组织特异的microRNA互补序列插入溶瘤病毒的基因组3’端,再将该病毒感染肿瘤患者小鼠。重组的病毒在皮下组织里具有正常的活性,能引发小鼠致死性的肌炎,和病毒血症。但是,在表达肌肉组织特异microRNA的细胞里,重组病毒无法复制并且不引起致死性的肌炎。发生这些改变不是因为病毒毒性致弱,而是互补的microRNA发挥了相应的作用。
研究者认为,改造的病毒可能成为新的载体系统,靶向治疗癌症。通过小鼠实验,研究者发现该载体效率高,且不产生毒副作用。
梅奥研究员称,以插入microRNA的病毒为载体,可用于癌症治疗,或是制备安全高效的疫苗。
原文摘要:Engineering microRNA responsiveness to decrease virus pathogenicity
【Abstract】
The cellular tropisms of eukaryotic viruses are shaped by their need for entry receptors and intracellular transcription factors. Here we show that viral tropisms can also be regulated by tissue-specific microRNAs (miRNAs). Target sequences complementary to muscle-specific miRNAs were inserted into the 3|[prime]| untranslated region (UTR) of an oncolytic picornavirus that causes lethal myositis in tumor-bearing mice. The recombinant virus still propagated in subcutaneous tumors, causing total regression and sustained viremia, but could not replicate in cells expressing complementary miRNAs and therefore did not cause myositis. This altered tropism was not due to insertional attenuation, as a control virus containing a 3|[prime]| UTR insert with a disrupted miRNA target sequence fully retained its lethal myotropism. Tissue-specific destabilization of viral genomes by miRNA target insertion provides a potentially versatile new mechanism for controlling the tropism of replicating viruses for therapy and may serve as a new modality for attenuating viruses for vaccine purposes.