Autonomous RNA-Mediated Anti-Influenza A Virus Therapeutics (AMRed Therapeutics)

自主RNA介导的抗甲型流感病毒疗法（AMRed Therapeutics）

• 批准号: 10005678
• 负责人: Brandy Lynn Houser
• 金额: $ 25.84万
• 依托单位: CELDARA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-17 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005678
• 关键词: Address; Affinity; Animals; Antibodies; Area; Automobile Driving; Binding; Biology; Biotechnology; Body Weight decreased; California; Caring; Cell-Mediated Cytolysis; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemistry; Coin; Collection; Communication; Coupled; Development; Disease Outbreaks; Engineering; Event; Evolution; Fibroblasts; Future; Gene Expression; Genes; Goals; Hong Kong; Hospitalization; Human; Immune response; In Vitro; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Invertebrates; Lead; Letters; Libraries; Lung; Mammalian Cell; Measures; Mediating; Medical; Modeling; Mus; National Institute of Allergy and Infectious Disease; Nature; Open Reading Frames; Phase; Plants; Polymerase; Population; Production; Property; Proteins; RNA; RNA Polymerase I; RNA Viruses; RNA amplification; RNA-Directed RNA Polymerase; Replicon; Research; Safety; Seasons; Signal Transduction; Technology; Therapeutic; Time; Turnip - dietary; United States National Institutes of Health; Untranslated RNA; Vaccines; Variant; Viral; Viral load measurement; Virus; anti-influenza; arm; base; cell type; combat; design; efficacy study; gene product; in vivo; infection rate; influenza virus vaccine; interest; macrophage; medical schools; member; mortality; neutralizing antibody; novel; novel therapeutics; novel vaccines; pandemic disease; pandemic influenza; preclinical development; prevent; product development; programs; seasonal influenza; stem; swine flu; synthetic biology; therapeutic gene; therapy development

Project Summary The NIAID has made one of its highest priorities the development of a universal influenza treatment. Current therapeutic strategies for timely neutralization of influenza A virus (IAV), the causative agent of both seasonal and pandemic flu, have been minimally effective. Moreover, seasonal flu vaccine strategies are typically less than 50% effective. Therefore, there continues to be an urgent need to generate both novel vaccine and therapeutic strategies against IAV to prevent and combat large scale outbreaks. We propose to advance our product, CM-BT1, through proof-of-concept mouse studies that will demonstrate rapid neutralization of IAV. CM-BT1 is a self-amplifying RNA replicon capable of driving host cell production of a protein, specifically a broadly neutralizing anti- HA stalk antibody. CM-BT1 is a member of our proprietary library of replicons, modified RNA dependent RNA polymerases (RdRp) derived from a diverse collection of plant and invertebrate viruses. CM-BT1, our lead product, stems from turnip crinkle virus (TCV) and has been demonstrated to successfully generate an RNA capable of self-replication and protein production in healthy mouse lungs in vivo. Importantly, we have also demonstrated safety in that CM-BT1 can be turned off when engineered with additional open reading frames and a self-targeting cassette that enables complete control of replicon activity without inducing any overt cytopathic effects to cells. The use of RNA as a therapeutic platform is an exciting new area of therapeutics made possible by recent advances in chemistry and synthetic biology. However, this potential therapeutic platform still remains somewhat limited in scope, owing largely to the short- lived nature of RNA. Our platform technology, and lead product, CM-BT1, overcomes these limitations through ongoing and controlled production of relevant gene products that can function for days, weeks, or possibly months. The purpose of this proposal is to demonstrate proof-of-concept in vivo using two lethal challenge IAV models. Using go/no-go criteria, CM-BT1 will be advanced through rigorous product development culminating in an efficacy study that will enable the launch of this product into full scale preclinical development for timely therapeutic neutralization of IAV.

项目摘要 NIAID已将开发通用流感作为其最高优先事项之一 治疗及时中和甲型流感病毒的当前治疗策略 (IAV)季节性流感和大流行性流感的病原体， 有效此外，季节性流感疫苗策略的有效性通常低于50%。 因此，仍然迫切需要产生新的疫苗， 针对IAV的治疗策略，以预防和对抗大规模爆发。 我们建议通过概念验证小鼠研究来推进我们的产品CM-BT 1 能迅速中和IAV病毒CM-BT 1是一种自扩增RNA复制子 能够驱动宿主细胞产生蛋白质，特别是广泛中和的抗- HA茎抗体。CM-BT 1是我们专有的复制子库的成员，经修饰 RNA依赖性RNA聚合酶（RdRp）来源于不同的植物集合， 无脊椎动物病毒CM-BT 1是我们的主导产品，来源于芜菁皱缩病毒（TCV）， 已经证明成功地产生了能够自我复制的RNA， 在健康小鼠体内肺部的蛋白质产生。重要的是，我们还证明了 安全性在于，当设计有额外的开放阅读时，CM-BT 1可以关闭 框架和能够完全控制复制子活性的自靶向盒 而不诱导任何明显的细胞病变效应。 使用RNA作为治疗平台是一个令人兴奋的新的治疗领域， 化学和合成生物学的最新进展使之成为可能。然而，这种潜力 治疗平台的范围仍然有限，主要是由于短， RNA的本质我们的平台技术和主导产品CM-BT 1克服了 这些限制通过相关基因产物的持续和受控生产来实现， 可以持续几天几周甚至几个月这项建议的目的是 使用两种致死性攻击IAV模型证明体内概念验证。使用 通过/不通过标准，CM-BT 1将通过严格的产品开发来推进 最终进行功效研究，使该产品能够全面上市， 大规模的临床前开发，用于及时治疗IAV的中和。