PANACEA Broad-spectrum Antiviral Therapeutics

PAACEA 广谱抗病毒疗法

• 批准号: 8617037
• 负责人: Todd H. Rider
• 金额: $ 17.29万
• 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/8617037
• 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.

尽管人们对新出现的病毒和NIAID A-C类优先病原体清单上的病毒非常关注，但针对这些病毒的预防或治疗药物相对较少，而且大多数存在的药物都是高度病原体特异性的，或者有不良副作用或其他缺点。我们已经开发出一种全新的广谱抗病毒治疗/预防药物，它有可能彻底改变病毒感染的治疗，包括那些由于新出现的、a - c类和常见临床病原体引起的感染。