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: 9150544
• 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/9150544
• 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; Health; Immune; Immune response; Immune system; Interferon Type I; 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; Recombinant Interferon; Recombinants; Research; Route; Safety; System; Testing; Therapeutic; Therapeutic Agents; Tissues; Transcript; Translations; Universities; Untranslated Regions; 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; 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（由申请人提供）：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，强调 VSV 溶瘤活性的机制可能涉及调节 I 型干扰素（IFN）的先天免疫系统缺陷。我们通过开发表达天然免疫基因（例如 IFNβ）的 VSV 来利用这一缺陷。由于现有的细胞缺陷阻止了 IFN 抗病毒功能，因此该病毒在恶性细胞中具有溶瘤活性。然而，由于病毒产生的外源性 IFN 阻止了病毒在正常细胞中的复制，因此我们现在已经产生了一种表达新的 VSV 载体。 IFNβ 及其病毒基因 3-UTR 区域中的 miR124 靶序列在正常神经组织中表达，但在神经元来源的癌症组织中不表达。我们的初步数据表明，VSV-miR124-IFN 的减弱程度甚至比 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 治疗中结合使用 I 型 IFN 和 miRNA 导致了胶质母细胞瘤。开发一种可能有助于治疗转移性疾病和胶质母细胞瘤的更具体的癌症病毒，因此我们提出两个目标。 VSV-miR124-IFN 作为针对转移性疾病（包括黑色素瘤和乳腺癌）的全身治疗其次，我们将评估 VSV-miR124-IFN 作为治疗胶质母细胞瘤的潜在疗法的用途。