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

项目摘要 NIAID已将开发一种普遍的流感作为其最优先事项之一 治疗。及时中和甲型流感病毒的当前治疗策略 (IAV)，季节性和大流行性流感的病原体，一直是最低限度的 有效。此外，季节性流感疫苗策略通常不到50%有效。 因此，仍然迫切需要生产新型疫苗和 针对IAV的治疗策略，以预防和抗击大规模暴发。 我们计划通过概念验证小鼠研究来推进我们的产品CM-BT1 这将证明IAV的快速中和。CM-BT1是一种自我扩增的RNA复制子 能够推动宿主细胞产生一种蛋白质，特别是一种广谱中和抗- HA柄抗体。CM-BT1是我们专有复制库的成员，修改后 RNA依赖的RNA聚合酶(RdRp)来源于多种植物和 无脊椎动物病毒。CM-BT1，我们的主导产品，源于萝卜皱纹病毒(TCV)和 已经被证明成功地产生了一种能够自我复制和 体内健康小鼠肺内蛋白质的产生。重要的是，我们还展示了 当设计有额外开放读数时，CM-BT1中的安全可被关闭 帧和能够完全控制复制子活动的自定位盒式磁带 不会对细胞产生任何明显的细胞病变效应。 使用RNA作为治疗平台是治疗学的一个令人兴奋的新领域 化学和合成生物学的最新进展使这一目标成为可能。然而，这种潜力 治疗平台在范围上仍然有一定的限制，这主要是由于- RNA的活生生的本性。我们的平台技术和主导产品CM-BT1克服了 这些限制通过持续和受控的相关基因产品的生产来实现 可以工作几天、几周或几个月。这项建议的目的是 使用两种致命的IAV模型在体内进行概念验证。vbl.使用 通过严格的产品开发，CM-BT1将得到提升 最终完成一项功效研究，使该产品能够全面上市 及时中和治疗IAV的临床前研究进展。

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.