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

项目摘要 RSV是一种主要的全球威胁，占呼吸道疾病的很大一部分， 高危患者的死亡率。高致病性RSV感染导致急性肺损伤， LRTI和肺炎相关并发症。由于RSV的治疗方法非常有限， 和疗效，这种疾病的生理模型的发展是发展的关键 限制该病毒感染和相关病理的治疗剂。该提案将利用 在RumiViro的迷你肺平台上， 器官型人肺组织以模拟呼吸道病毒感染。该平台将 用于模拟生理肺组织中的RSV感染并确定治疗方法 疾病规模我们将首先筛选23,000种高度多样化的化合物， 表型文库的生物活性化合物，因为它们能够减轻RSV感染。击中 候选物将进一步验证其在微型细胞中抑制RSV的多种临床株的能力， 离体肺和原代肺组织。这项工作将产生变革性的影响， 治疗剂的后续开发，并将使治疗剂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II期研究中领导优化工作。这项工作将提供一个高效的 用于鉴定和开发RSV治疗剂的框架， 减轻风险患者中RSV诱导的病理的抗感染治疗剂。

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.