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

微芯片上的自组织合成人肺可抵抗 RSV 感染

基本信息

批准号：
10698767
负责人：
Fred Etoc
金额：
$ 30万
依托单位：
RUMI SCIENTIFIC, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-22 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10698767
关键词：
2019-nCoV Acute Lung Injury Air Anti-Infective Agents Biological Assay COVID-19 patient Cessation of life Child Clinical Collection Coronavirus Development Disease Disease model Drug Kinetics Elderly Epidemic Geometry Human Image Immunocompromised Host Individual Infection Integration Host Factors Interphase Libraries Life Style Liquid substance Lung Lung infections Mediating Modeling Molecular Organ Pathogenicity Pathology Patients Pharmaceutical Preparations Phase Phenotype Physiological Physiology Pneumonia Property Pulmonary Pathology Respiratory Disease Respiratory Syncytial Virus Infections Respiratory syncytial virus Risk Standardization Stimulus Structure of parenchyma of lung Testing Therapeutic Time Tissues Validation Viral Viral Respiratory Tract Infection Virus Virus Diseases Virus Inhibitors Work antiviral drug development bronchial epithelium candidate validation drug development drug metabolism fighting follow-up future epidemic future outbreak high throughput screening human disease human pluripotent stem cell in vivo in vivo Model lead optimization microchip mortality novel outbreak control phase 2 study physiologic model potency testing rational design respiratory respiratory infection virus respiratory virus response screening self organization small molecule therapeutic candidate therapeutic development tool viral transmission

项目摘要

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.

项目概要 RSV 是一种主要的全球威胁，导致呼吸道疾病和高致病性 RSV 感染导致急性肺损伤的患者死亡， LRTI 和肺炎相关并发症由于 RSV 治疗的使用非常有限。和疗效，建立该疾病的生理模型是开发的关键该提案将利用限制这种病毒感染和相关病理的疗法。 RumiViro 的迷你肺平台可提供源源不断的基因匹配信息该平台将用于模拟呼吸道病毒感染的器官型人体肺组织。用于模拟生理性肺组织中的 RSV 感染并确定治疗方法我们将首先筛选 23,000 种高度多样化的化合物。具有减轻 RSV 感染能力的生物活性化合物表型库。候选者将进一步验证其在小型试验中抑制 RSV 多种临床菌株的能力。这项工作将对离体肺和原代肺组织产生变革性影响。随后开发治疗方法并将进一步验证治疗方法基于药物代谢、药代动力学分析、体内概念验证和这项工作将为后续第二阶段研究提供高效的先导优化工作。 RSV 疗法的识别和开发框架，有望发现抗感染疗法可减轻高危患者由 RSV 引起的病理。