PANACEA Broad-spectrum Antiviral Therapeutics

PAACEA 广谱抗病毒疗法

• 批准号: 8432129
• 负责人: Todd H. Rider
• 金额: $ 40.58万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8432129
• 关键词: Adverse effects; Animal Model; Antiviral Agents; Apoptosis; Arenavirus; Caspase; Categories; Cells; Clinical; Dengue; Dengue Virus; Disadvantaged; Double-Stranded RNA; Drug Kinetics; Family; Flavivirus; Goals; In Vitro; Influenza; Influenza A Virus, H1N1 Subtype; Instruction; Lymphocytic choriomeningitis virus; Mammalian Cell; Mission; Mus; National Institute of Allergy and Infectious Disease; New England; Orthobunyavirus; Production; Protocols documentation; Quality Control; Testing; Therapeutic; Viral; Virus; Virus Diseases; Work; biodefense; cell type; hemorrhagic fever virus; immunogenicity; in vivo; interest; killings; member; mouse model; pathogen; prophylactic; success

Although there is great concern over emerging viruses and viruses on the NIAID category A-C priority pathogen lists, there are relatively few prophylactics or therapeutics for these viruses, and most which do exist are highly pathogen-specific or have undesirable side effects or other disadvantages. We have developed a radically new and very broad-spectrum antiviral therapeutic/prophylactic that has the potential to revolutionize the treatment of viral infections, including those due to emerging, category A-C, and common clinical pathogens. Our dsRNA (double-stranded RNA) activated caspase (DAC) approach selectively induces apoptosis in cells containing any viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have previously created a DAC and shown that it is nontoxic and effective against 10 different viruses in 10 mammalian cell types. We have also demonstrated that it is nontoxic in mice and rescues mice from a lethal H1N1 influenza challenge. A large number of viruses on the category A-C lists belong to the arenavirus, bunyavirus, and flavivirus families, virus families against which we have not previously tested DAC. Therefore, the experimental focus of this proposal is to test DAC against representative members of these virus families. The specific aims are to: 1. Demonstrate efficacy in multiple mammalian cell types against representative members of the arenavirus, bunyavirus, and flavivirus families. 2. Perform DAC pharmacokinetic analyses and assess DAC immunogenicity in vivo. 3. Demonstrate antiviral efficacy in a lethal mouse model using the best challenge virus from the in vitro trials. Success in these aims should demonstrate the potential of DAC to treat arenaviruses, bunyaviruses, and flaviviruses and pave the way for further trials with additional viruses and animal models. This work should greatly advance DAC toward ultimate utility as a safe, broad-spectrum therapeutic/prophylactic for NIAID priority and emerging viral pathogens, filling a large gap in existing therapeutics and directly supporting NERCE's mission.

尽管对新出现的病毒和NIAID A-C类优先病原体列表上的病毒存在极大的关注，但针对这些病毒的药物或治疗剂相对较少，并且确实存在的大多数是高度病原体特异性的或具有不期望的副作用或其他缺点。我们开发了一种全新的、非常广谱的抗病毒治疗/预防药物，有可能彻底改变病毒感染的治疗，包括那些由于新兴的、A-C类和常见的临床病原体引起的病毒感染。 我们的dsRNA（双链RNA）激活的caspase（DAC）方法选择性地诱导含有任何病毒dsRNA的细胞凋亡，快速杀死感染的细胞而不伤害未感染的细胞。我们之前已经创造了一种DAC，并证明它对10种哺乳动物细胞类型中的10种不同病毒无毒且有效。我们还证明了它在小鼠中无毒，并能从致命的H1N1流感攻击中拯救小鼠。A-C类列表中的大量病毒属于沙粒病毒、布尼亚病毒和黄病毒家族，我们以前没有对DAC进行过检测。 因此，本提案的实验重点是针对这些病毒家族的代表性成员测试DAC。具体目标是： 1.证明在多种哺乳动物细胞类型中对代表性的 沙粒病毒、布尼亚病毒和黄病毒科。 2.进行DAC药代动力学分析并评估DAC体内免疫原性。 3.使用体外试验中最佳攻毒病毒在致死小鼠模型中证明抗病毒疗效。 这些目标的成功应该证明DAC治疗沙粒病毒、布尼亚病毒和黄病毒的潜力，并为使用其他病毒和动物模型进行进一步试验铺平道路。这项工作将极大地推动DAC作为NIAID优先和新兴病毒病原体的安全，广谱治疗/预防的最终用途，填补现有治疗方法的巨大空白，并直接支持NERCE的使命。