Self-organizing synthetic human lungs on microchips to fight infection by RSV

项目摘要 呼吸道合胞病毒是一种主要的全球威胁，在呼吸道疾病和 高危患者的死亡率。高致病性呼吸道合胞病毒感染导致急性肺损伤， LRTI和肺炎相关并发症。由于RSV的治疗方法在使用上非常有限 而疗效、生理学模型的发展是本病发展的关键 限制这种病毒感染和相关病理的治疗方法。这项提议将使 在RumiViro的迷你肺平台上，提供取之不尽的基因匹配 用于模拟呼吸道病毒感染的器官型人肺组织。这个平台将是 被用来模拟生理性肺组织中的RSV感染并确定治疗方法 大规模的疾病。我们将首先筛选23,000个高度多样化的化合物的集合 生物活性化合物的表型文库，用于减轻RSV感染的能力。命中 候选者将进一步验证他们抑制多种临床RSV毒株的能力。 肺和原发肺组织体外培养。这项工作将对 治疗学的后续发展，并将使治疗的进一步验证成为可能 基于药物代谢、药代动力学分析、体内概念验证和 在后续阶段2研究中领导优化工作。这项工作将提供一个高效的 呼吸道合胞病毒疗法的识别和发展框架，有望找到 抗感染治疗，以减轻RSV诱导的高危患者的病理。

Project Summary RSV is a major global threat that accounts for a significant share of respiratory disease and mortality among patients at risk. Infection by highly pathogenic RSV results in acute lung injury, LRTI, and pneumonia-associated complications. As treatments for RSV are very limited in use and efficacy, the development of physiological models of this disease is key to develop therapeutics that limit infection by this virus and associated pathology. This proposal will capitalize on RumiViro’s mini-lung platform that offers inexhaustible access to genetically matched organotypic human lung tissue to model infection by respiratory viruses. This platform will be deployed to model RSV infection in physiological lung tissue and identify therapeutics for this disease at scale. We will first screen a collection of 23,000 compounds of a highly diverse phenotypic library of bioactive compounds for their ability to mitigate infection by RSV. Hit candidates will be further validated for their ability to inhibit multiple clinical strains of RSV in mini- lungs and primary lung tissue ex vivo. This work will have transformative influence for the subsequent development of therapeutics and will enable further validation of therapeutic candidates based on drug metabolism, pharmacokinetic analysis, in vivo proof-of-concept and lead optimization efforts in follow-up Phase 2 studies. This work will provide a highly efficient framework for the identification and development of RSV therapeutics with the promise of finding anti-infective therapeutics that mitigate the RSV-induced pathology in patients at risk.