Morpholino Antisense Drugs for Hepatitis C Virus

治疗丙型肝炎病毒的吗啉代反义药物

• 批准号: 6787453
• 负责人: Nigel Bourne
• 金额: $ 16.41万
• 依托单位: AVI BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6787453
• 关键词: antisense nucleic acid; antiviral agents; bioassay; cell line; drug design /synthesis /production; genetic transcription; genetic translation; genetically modified animals; genotype; hepatitis C virus; laboratory mouse; nucleic acid sequence; peptide analog; pharmacokinetics; posttranslational modifications; protein structure; ribosomal RNA; southern blotting; transfection /expression vector; virus replication

DESCRIPTION (provided by applicant): Hepatitis C Virus (HCV) causes a persistent infection in most humans exposed to the virus. HCV infection in time can lead to cirrhosis and hepatocellular carcinoma. Although the annual number of newly infected patients has dropped significantly over the past decade, about 4 million people are currently persistently infected in the USA. There is presently no universal drug available to treat HCV infections. The current treatment regimen for HCV is based on a combination of pegylated interferon and ribavirin. However, even this improved combination of drugs is not able to clear HCV in all patients. About 50% of patients do not respond to the treatment. Even more problematic is that, based on the state of their liver disease, some patients cannot be treated with interferon, as this will enhance the disease. In addition, some genotypes have shown particular resistance to interferon/ribavirin treatment. Experience obtained from drug development with other RNA viruses has shown these viruses readily generate variants that show resistance to protease and polymerase inhibitors. The long-term goal of our research is to develop HCV-specific phosphorodiamidate morpholino antisense oligomer (PMO) drugs targeting replication and translation signals. The specific aims proposed are to design and assess the efficacy of antisense PMO oligomers targeting HCV RNA signals with tissue culture-based replication and translation assays. These assays will be used to examine the efficacy and possible toxicity of the PMOs. PMOs are analogs of short DNA oligomers with modified sugar and phosphate moieties in the nucleotides, resulting in high specific binding and complete resistance to nucleases in the host. PMOs have been used to inhibit the movement of scanning ribosomes. Their safety, efficacy, and bioavailability make these compounds great candidates for clinical applications. No small animal models are available to study HCV. We will initially evaluate a panel of PMOs in tissue culture replication and translation models. We will use a transgenic mouse model to evaluate the safety and efficacy of these compounds in animals. The proposed research, if successful, would lead to a application for Phase II funding to bring the use of PMOs into the HCV drug market and provide a well-tolerated, inexpensive alternative to current HCV treatments.

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)在大多数接触该病毒的人中引起持续感染。丙型肝炎病毒感染及时可导致肝硬变和肝细胞癌。尽管在过去十年中，每年新感染患者的数量显著下降，但目前美国约有400万人持续感染。目前还没有治疗丙型肝炎病毒感染的通用药物。目前丙型肝炎病毒的治疗方案是基于聚乙二醇化干扰素和利巴韦林的组合。然而，即使是这种改进的药物组合也不能在所有患者中清除丙型肝炎病毒。大约50%的患者对治疗没有反应。更有问题的是，根据他们的肝脏疾病状态，一些患者不能使用干扰素治疗，因为这会加剧疾病。此外，一些基因类型对干扰素/利巴韦林治疗表现出特别的耐药性。从其他RNA病毒的药物开发中获得的经验表明，这些病毒很容易产生对蛋白酶和聚合酶抑制剂具有耐药性的变种。我们研究的长期目标是开发针对复制和翻译信号的丙型肝炎病毒特异性磷酸二酯吗啉反义寡聚体(PMO)药物。提出的具体目的是设计和评估针对丙型肝炎病毒RNA信号的反义PMO寡聚体的有效性，方法是基于组织培养的复制和翻译分析。这些检测将被用来检查PMOS的有效性和可能的毒性。PMOS是核苷酸中带有修饰的糖和磷酸部分的短DNA低聚物的类似物，导致对宿主中的核酸酶具有高特异性结合和完全抗性。PMOS已被用来抑制扫描核糖体的运动。它们的安全性、有效性和生物利用度使这些化合物成为临床应用的极佳候选者。目前尚无小型动物模型可用于研究丙型肝炎病毒。我们将初步评估一组PMO在组织培养、复制和翻译模型中的作用。我们将使用转基因小鼠模型来评估这些化合物在动物身上的安全性和有效性。这项拟议的研究如果成功，将导致申请第二阶段资金，将PMOS的使用引入丙型肝炎药物市场，并提供一种耐受性良好、价格低廉的替代目前的丙型肝炎治疗方法。