SUMMARY: Researchers from UCLA’s Department of Molecular and Medical Pharmacology in collaboration with external collaborators have developed a platform for complex testing of antiviral agents in multiple cell models. Currently this technology is optimized for Coronavirus-type strains, but the system can easily be adapted to other viral pathogens. BACKGROUND: Recent research on SARS-CoV-2 has shown that following initial virus infection in the upper respiratory airways, the viral infection further progresses to additional organ systems implicating a variety of tissue and cell types, most prominently lung, heart, brain, kidneys, and some gastrointestinal tissues. While it is still unclear whether the damage to tissue outside of the lungs is a result of downstream secondary complications or attributed to damage directly caused by the virus. The multiple tissue types implicated in viral infection highlight the need for diversity in in vitro cell-types and tissues used in research on the virus and testing of antiviral treatments. Current base-line research approaches used by many labs consist of immortalized-cell lines in culture plates which are insufficient for proper characterization. For example, the human respiratory system consists of complex tissues and various cell types necessary for gas exchange, and which are better recapitulated by using more complex patient derived in vitro models such as 3D organoid cultures or microfluidic organ-on-chip. These novel models can be generated in such a manner so as to enrich for relevant cells possessing the ACE2 receptor utilized by the virus as a point of entry. This need for more complex in vitro research approaches applies to other tissue and organ system, and a successful screening system incorporates these approaches employing various tissue-types to better assess the efficacy of the tested antivirals. INNOVATION: UCLA researchers have developed a platform that utilizes 3D organoid culture, in addition to organ-on-chip models, for the functional analysis of coronaviruses on multiple cell types including lung epithelial progenitor cells. This platform utilizes patient derived tissues and uses a tissue dissociation and cellular fractionation approach to allow for selection and enrichment of epithelial cells from proximal and distal regions of the human lung. Additional cell types such as cardiac myocytes (heart cells) and pancreas cells are derived from induced pluripotent cells (iPSCs), and the platform also incorporates human proximal tubule cells and kidney cells, as well as limbal stem cells from various sources. Together these allow for rapid analysis of SARS-CoV-2 virus infection in 2D, 3D and microfluidic CHIP culture to better understand the susceptibility and tissue injury mechanisms of this or similar viral pathogens. This same system allows for antiviral drug screening to better identify more clinically relevant compounds to treat COVID-19. POTENTIAL APPLICATIONS: • System for testing antiviral agents. • Platform for researching effect of viral agents on numerous tissue types rapidly.
ADVANTAGES: • Assessment of drugs in numerous organ systems and tissue types: providing a more holistic assessment of toxicity and efficacy of antiviral agents. • Allows testing both biological and chemical compounds. • Allows for rapid identification of compounds which are either tissue specific or more generalizable DEVELOPMENT-TO-DATE: A functional platform has been developed and deployed for testing in internal research laboratories serving as a successful proof of concept. Various compounds have been tested, both biological and chemical based, and results have provided fruitive research leads.