Vesicular Stomatitis Virus (VSV) Replication in Malignant Cells

 描述（由申请方提供）：我们的数据表明，水泡性口炎病毒（VSV）是根除恶性细胞的有效药物。VSV溶瘤活性的机制可能涉及先天免疫系统的缺陷，调节I型干扰素（IFN）的产生，控制抗病毒基因的诱导。我们开发了表达先天免疫基因（如IFNβ）的VSV，从而利用了这一缺陷。由于存在阻止IFN抗病毒功能的细胞缺陷，该病毒在恶性细胞中保持溶瘤活性。然而，由于病毒产生的外源性IFN阻止病毒在正常细胞中复制，因此病毒是极度减毒的。基于这些发现，我们现在已经产生了一种新的VSV载体，其在其病毒基因的3-UTR区域中表达IFNβ以及miR 124靶序列。miR 124在正常神经元组织中表达，但在神经元衍生的癌组织如胶质母细胞瘤中不表达。我们的初步数据表明，VSV-miR 124-IFN甚至比VSV-IFN更弱，因为普遍的miRNA抑制中枢神经系统中的病毒复制。在VSV治疗中使用I型IFN以及miRNA的组合已经导致了更特异性的癌症病毒的开发，其可用于治疗转移性疾病以及胶质母细胞瘤。因此，我们提出两个目标。首先，我们将评估VSV-miR 124-IFN作为针对转移性疾病（包括黑色素瘤和乳腺癌）的全身治疗的用途。其次，我们将评估VSV-miR 124-IFN作为治疗胶质母细胞瘤的潜在治疗剂的用途。

 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.