Vesicular Stomatitis Virus (VSV) Replication in Malignant Cells

水泡性口炎病毒 (VSV) 在恶性细胞中的复制

• 批准号: 9339626
• 负责人: Glen N. Barber
• 金额: $ 33.24万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339626
• 关键词: 3' Untranslated Regions; Adverse effects; Antiviral Agents; Apoptotic; Attenuated; Breast Adenocarcinoma; Cause of Death; Cell Death; Cells; Clinic; Clinical Data; Collaborations; Constitution; Cytolysis; Cytoplasm; Data; Defect; Development; Diagnosis; Disease; Dose; Exhibits; Generations; Genes; Genetic; Glioblastoma; Glioma; Immune; Immune response; Immune system; Innate Immune System; Interferon Type I; Interferon-alpha; Interferons; Intravenous; Knowledge; Laboratories; Macaca; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; MicroRNAs; Mus; Natural Immunity; Neoplasm Metastasis; Neuraxis; Neurons; Neuropathy; Normal Cell; Oncolytic; Organism; Phase I Clinical Trials; Predisposition; Primary carcinoma of the liver cells; Production; Property; RNA Viruses; Recombinants; Research; Route; Safety; System; Testing; Therapeutic; Therapeutic Agents; Tissues; Transcript; Translations; Universities; Vesicular stomatitis Indiana virus; Viral; Viral Genes; Virus; Virus Replication; adaptive immunity; attenuation; base; cancer cell; cancer therapy; cell transformation; chemotherapeutic agent; melanoma; mouse model; neoplastic cell; next generation; novel therapeutics; oncolytic Vesicular Stomatitis Virus; phase I trial; pre-clinical; prevent; public health relevance; recombinant virus; response; tumor; vector

 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.

 描述（由适用提供）：我们的数据表明囊泡性口腔炎病毒VSV是消除恶性细胞的潜在药物。强调VSV溶瘤活性的机制可能涉及先天免疫系统中的缺陷，调节I型干扰素（IFN）的生产，以控制诱导抗病毒基因的诱导。我们已经通过开发表达先天免疫基因（例如IFNβ）的VSV来探讨了这一缺陷。由于现有的细胞缺陷，该病毒在恶性细胞中保持溶瘤活性，从而预防IFN抗病毒功能。然而，由于病毒产生的外源性IFN可防止正常细胞中的病毒复制，因此该病毒受到极大的衰减。基于这些发现，我们现在产生了一种新的VSV载体，该载体在其病毒基因的3-UTR区域中表达IFNβ以及MiR124靶序列。 miR124在正常的神经元组织中表达，但不表达神经元衍生的癌组织，例如胶质母细胞瘤。我们的初步数据表明，VSV-MIR124-IFN比VSV-IFN更衰减，因为普遍的miRNA抑制了中枢神经系统中的病毒复制。在VSV疗法中使用I型IFN以及miRNA的组合导致了更具体的癌症病毒的发展，该病毒可能对转移性疾病和胶质母细胞瘤的治疗可能有用。因此，我们提出了两个目标。首先，我们将评估VSV-MIR124-IFN用作针对转移性疾病在内的全身治疗，包括黑色素瘤和乳腺癌。其次，我们将评估VSV-MIR124-IFN作为治疗胶质母细胞瘤的潜在治疗方法的使用。