Morpholino Antisense Drugs for Hepatitis C Virus

描述（由申请方提供）：丙型肝炎病毒（HCV）在大多数暴露于该病毒的人中引起持续感染。HCV感染的时间可以导致肝硬化和肝细胞癌。尽管在过去十年中，每年新感染患者的数量显著下降，但美国目前仍有约400万人持续感染。目前还没有治疗HCV感染的通用药物。目前HCV的治疗方案是基于聚乙二醇干扰素和利巴韦林的组合。然而，即使这种改进的药物组合也不能清除所有患者的HCV。大约50%的患者对治疗没有反应。更大的问题是，根据他们的肝病状态，一些患者不能用干扰素治疗，因为这会加重疾病。此外，一些基因型已经显示出对干扰素/利巴韦林治疗的特定抗性。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抗性的变体。我们的长期研究目标是开发针对HCV复制和翻译信号的磷酰二胺吗啉反义寡聚体（PMO）药物。提出的具体目标是设计和评估反义PMO寡聚体靶向HCV RNA信号与组织培养为基础的复制和翻译测定的疗效。这些试验将用于检查PMO的有效性和可能的毒性。PMO是短DNA寡聚体的类似物，在核苷酸中具有修饰的糖和磷酸部分，导致对宿主中核酸酶的高度特异性结合和完全抗性。PMO已被用于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理想候选物。没有小动物模型可用于研究HCV。我们将首先评估一组组织培养复制和翻译模型中的PMO。我们将使用转基因小鼠模型来评估这些化合物在动物中的安全性和有效性。这项研究如果成功，将导致申请第二阶段资金，将PMO的使用带入HCV药物市场，并为目前的HCV治疗提供一种耐受性良好，价格低廉的替代方案。

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.