Vesicular Stomatitis Virus (VSV) Replication in Malignant Cells

 描述(由申请人提供)：我们的数据表明水泡性口炎病毒，VSV，是一种有效的药物来根除恶性细胞。VSV溶瘤活性的机制可能涉及先天免疫系统的缺陷，它调节I型干扰素(IFN)的产生，从而控制抗病毒基因的诱导。我们已经利用了这一缺陷，开发了表达先天性免疫基因的VSV，如干扰素β。由于现有的细胞缺陷阻碍了干扰素的抗病毒功能，这种病毒在恶性肿瘤细胞中保持着溶瘤活性。然而，由于病毒产生的外源干扰素阻止了病毒在正常细胞中的复制，因此病毒被极大地减弱了。基于这些发现，我们现在已经构建了一种新的VSV载体，该载体在其病毒基因的3-UTR区表达干扰素β和miR124靶序列。MiR124在正常神经元组织中表达，但在胶质母细胞瘤等神经源性肿瘤组织中不表达。我们的初步数据表明，VSV-miR124-干扰素比VSV-干扰素更弱，因为普遍存在的miRNAs抑制了病毒在中枢神经系统的复制。在VSV治疗中使用I型干扰素和miRNAs的结合导致了一种更特异的癌症病毒的开发，这种病毒可能对转移性疾病和胶质母细胞瘤的治疗有用。因此，我们提出了两个目标。首先，我们将评估VSV-miR124-干扰素作为全身治疗包括黑色素瘤和乳腺癌在内的转移性疾病的使用。其次，我们将评估VSV-miR124-干扰素作为治疗胶质母细胞瘤的潜在治疗方法的应用。

 DESCRIPTION (provided by applicant): Our data indicate that vesicular stomatitis virus, VSV, is a potent agent in the eradication of malignant cells. The mechanisms underlining VSV oncolytic activity may involve flaws in the innate immune system, regulating type I interferon (IFN) production that controls the induction of anti-viral genes. We have exploited this defect by developing VSV that expresses innate immune genes such as IFNβ. This virus maintains oncolytic activity in malignant cells due to existing cellular defects that prevent IFN antiviral function. However, the virus is extremely attenuated since viral produced exogenous IFN prevents viral replication in normal cells. Based on these findings, we have now generated a new VSV vectors that express IFNβ as well as miR124 target sequences in the 3-UTR region of their viral genes. MiR124 is expressed in normal neuronal tissue, but not neuronal derived cancer tissue such as glioblastoma. Our preliminary data indicates that VSV-miR124-IFN is even more attenuated than VSV-IFN because prevalent miRNAs suppress viral replication in the central nervous system. The combination of using type I IFN as well as miRNAs in VSV therapeutics has led to the development of a more specific cancer virus that may be useful for the treatment of metastatic disease as well as glioblastoma. We thus propose two aims. First, we will evaluate the use of VSV-miR124-IFN as a systemic treatment against metastatic disease including melanoma and breast adenocarcinoma. Second, we will evaluate the use of VSV-miR124-IFN as a potential therapeutic to treat glioblastoma.