Lassa-vesicular stomatitis chimeric virus safely destroys brain tumors.
Lassa-vesicular stomatitis chimeric virus safely destroys brain tumors.
复制标题
拉沙水泡性口炎嵌合病毒可以安全地破坏脑肿瘤。
DOI：
10.1128/jvi.00709-15
复制
发表时间：
2015
影响因子：
5.4
通讯作者：
vandenPol,AnthonyN
中科院分区：
文献类型：
--
作者：
Wollmann,Guido;Drokhlyansky,Eugene;Davis,JohnN;Cepko,Connie;vandenPol,AnthonyN
大脑中的高级肿瘤是最致命的癌症之一。在这里，我们采用了一种有前途的溶瘤病毒——水泡性口炎病毒（VSV），并测试了这样的假设：通过用来自五种不同病毒（包括埃博拉病毒、马尔堡病毒、淋巴细胞脉络膜脑膜炎病毒（LCMV）、狂犬病病毒和拉沙病毒）之一的糖蛋白取代亲神经VSV糖蛋白，可以消除与该病毒相关的神经毒性，而不阻断其在大脑中的溶瘤潜力。基于正常细胞和肿瘤细胞的体外感染，我们选择了两种病毒进行体内测试。野生型 VSV 直接注射到大脑中是致命的。相比之下，一种含有拉沙病毒糖蛋白前体（GPC）和VSV基因的新型嵌合病毒（VSV-LASV-GPC）在脑内或脑外均未表现出不良作用，并且能够靶向并完全摧毁脑癌，包括高级别胶质母细胞瘤和黑色素瘤，甚至在转移性癌症模型中也是如此。当小鼠患有两个脑肿瘤时，在一个肿瘤（神经胶质瘤或黑色素瘤）中进行 VSV-LASV-GPC 瘤内注射会导致肿瘤完全破坏；重要的是，病毒在大脑内向对侧移动，选择性地感染第二个未注射的肿瘤。将VSV基因与编码埃博拉病毒糖蛋白的基因相结合的嵌合病毒在大脑中是安全的，并且还选择性地靶向脑肿瘤，但在破坏脑肿瘤和延长荷瘤小鼠的存活方面的效果要差得多。对多种癌症类型的趋向性与精致的肿瘤特异性相结合，为 VSV-LASV-GPC 作为脑内安全有效的溶瘤嵌合病毒的广泛应用打开了新的大门。重要性许多病毒已经过测试其靶向和杀死癌细胞的能力。水泡性口炎病毒（VSV）已显示出巨大的希望，但一个关键问题是，如果它进入大脑，可能会产生不良的神经系统后果，包括死亡。我们测试了一系列含有编码VSV基因的嵌合病毒，以及编码其他病毒糖蛋白的基因，包括埃博拉病毒、拉沙病毒、LCMV、狂犬病病毒和马尔堡病毒，这些病毒取代了VSV糖蛋白基因。埃博拉和拉沙嵌合病毒在大脑中是安全的，并且靶向脑肿瘤。 Lassa-VSV 特别有效，即使直接注射到大脑中也没有显示出不良副作用，并且能够靶向并消灭两种不同类型的致命脑癌，包括胶质母细胞瘤和黑色素瘤。
High-grade tumors in the brain are among the deadliest of cancers. Here, we took a promising oncolytic virus, vesicular stomatitis virus (VSV), and tested the hypothesis that the neurotoxicity associated with the virus could be eliminated without blocking its oncolytic potential in the brain by replacing the neurotropic VSV glycoprotein with the glycoprotein from one of five different viruses, including Ebola virus, Marburg virus, lymphocytic choriomeningitis virus (LCMV), rabies virus, and Lassa virus. Based onin vitroinfections of normal and tumor cells, we selected two viruses to testin vivo. Wild-type VSV was lethal when injected directly into the brain. In contrast, a novel chimeric virus (VSV-LASV-GPC) containing genes from both the Lassa virus glycoprotein precursor (GPC) and VSV showed no adverse actions within or outside the brain and targeted and completely destroyed brain cancer, including high-grade glioblastoma and melanoma, even in metastatic cancer models. When mice had two brain tumors, intratumoral VSV-LASV-GPC injection in one tumor (glioma or melanoma) led to complete tumor destruction; importantly, the virus moved contralaterally within the brain to selectively infect the second noninjected tumor. A chimeric virus combining VSV genes with the gene coding for the Ebola virus glycoprotein was safe in the brain and also selectively targeted brain tumors but was substantially less effective in destroying brain tumors and prolonging survival of tumor-bearing mice. A tropism for multiple cancer types combined with an exquisite tumor specificity opens a new door to widespread application of VSV-LASV-GPC as a safe and efficacious oncolytic chimeric virus within the brain.IMPORTANCEMany viruses have been tested for their ability to target and kill cancer cells. Vesicular stomatitis virus (VSV) has shown substantial promise, but a key problem is that if it enters the brain, it can generate adverse neurologic consequences, including death. We tested a series of chimeric viruses containing genes coding for VSV, together with a gene coding for the glycoprotein from other viruses, including Ebola virus, Lassa virus, LCMV, rabies virus, and Marburg virus, which was substituted for the VSV glycoprotein gene. Ebola and Lassa chimeric viruses were safe in the brain and targeted brain tumors. Lassa-VSV was particularly effective, showed no adverse side effects even when injected directly into the brain, and targeted and destroyed two different types of deadly brain cancer, including glioblastoma and melanoma.