Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics

Longlong Si; Haiqing Bai; Melissa Rodas; Wuji Cao; Crystal Yur Oh; Amanda Jiang; Atiq Nurani; Danni Y Zhu; Girija Goyal; Sarah Gilpin; Rachelle Prantil-Baun; Donald E. Ingber

Taken together, these data show that human lung Airway Chip may represent a more human-relevant preclinical tool that can be added to the current arsenal of assays available to virologists and drug developers for confronting present and future viral pandemics. Organ Chips could be particularly useful for identifying existing approved drugs that may be repurposed for pandemic virus applications in crisis situations such as we face today that require accelerated development of potential therapeutic and prophylactic interventions. For example, our work on repurposing of COVID19 therapeutics was initiated on January 13, 2020 (one day after the sequence was published 21 ), and our first results with drugs in Airway Chips were obtained 3 weeks later. One limitation of human Organ Chips is that they are a relatively low throughput model (12 chips can be run per automated culture instrument; 2-3 instruments per incubator) and it can take 2-3 weeks to differentiate the airway epithelium under an ALI on-chip before experiments can be initiated; however, the level of mimicry of human lung physiology and pathophysiology is extremely high as shown previously 6,7 and in the present study with various strains of infectious influenza virus. Established cell lines currently used in virology studies, such as the Huh-7 cells used here, offer a higher throughput approach for rapid screening, but they do not exhibit features of a functional human lung epithelium. Thus, a more effective discovery pipeline can be created by combining these approaches.