Airway-On-A-Chip Could Speed Up Future Drug and Therapy Development
CAMBRIDGE, Mass.—Developing a new drug is incredibly complex, but a new breakthrough could help scientists accelerate the process. Researchers at Draper have created a more accurate model of the human airway in a microfluidic device, providing a better platform to study how airway tissue cells respond to pathogens and drug therapies.
Most pharmaceutical screening methods depend on petri dishes in a lab or in animal models, but these environments aren’t always the best analog of how things work in live humans. As such, many drugs and treatments that seem promising in animals often fail when they reach human trials.
In recent years, scientists have developed a way to model organs and other body tissues on microfluidic chips, which provide a much closer comparison. These miniature human tissues
have so far included the liver, kidney, vasculature, tumor, colon and lung, and now Draper researchers have added new findings for the human airway with powerful implications for future application to high priority pathogen research.
The researchers cultured human primary bronchial epithelial cells under air-liquid interface (ALI) conditions inside a microphysiological system, or MPS, which is designed to mimic human physiology by precisely controlling an environment for cells. Originally, the team was investigating what happens to those cells when they were infected with SARS-CoV-2, but when the researchers fed a flow of therapies in, they discovered something unexpected.
The treated airway tissues showed that two seemingly promising therapies had failed to rein in the viral infection. Those therapies had worked well enough in preclinical studies to send them to human clinical trials, but they eventually failed when tested in humans. In other words, Draper’s airway tissue model accurately predicted the lack of efficacy of two therapies that other pre-clinical methods had failed to reveal.
On further examination, the team detected the airway infection did respond to three antiviral drugs that had succeeded in clinical trials and were now FDA-approved. In all five total cases, the antivirals performed as expected in comparison to clinical outcomes. Importantly, these outcomes were more accurate than those obtained from in vitro tissue models using MPS platforms other than Draper’s PREDICT96-ALI.
“This is the first report of comprehensive and accurate screening of therapeutic candidates for COVID-19 in an organ-on-chip,” said Christine Fisher, Group Leader of Microbiology and Immunology at Draper. “PREDICT96-ALI can increase clinical success, and that represents a new and major milestone in the effort to use human primary cell-based preclinical models to expedite countermeasure development for emerging infectious disease threats and, more broadly, in the drug development pipeline.”
MPS are promising for evaluating drugs before they go to clinical trials, according to Ashley Gard, Group Leader of Cellular and Tissue Engineering and Principal Biomedical Engineer at Draper. But a major limiting factor is the lack of preclinical models capable of providing data predictive of human clinical responses, she added. Writing in Advanced Biology, the researchers say, “There still exists a tremendous unmet need for predictive MPS airway models to fill a critical gap in preclinical therapeutic screening for COVID-19 and other emerging respiratory infections.”
Special care was taken to keep the airway tissue models thriving in the microenvironment of PREDICT96-ALI. The tissues “lived” in a culture media, bathed in a dynamic fluid flow and given nutrients and oxygen. They were tested in a biosafety level 3 (BSL-3) high-containment laboratory, which allowed researchers to evaluate the full viral life cycle of SARS-CoV-2, a critical step in assessing compounds. The paper builds on research published in the journal Cells in 2023.
The research paper, set for print publication in the journal Advanced Biology in August, concludes: “PREDICT96-ALI is a model of the human broncho-tracheal lung tissue capable of assessing the efficacy of SARS-CoV-2 therapeutics with sufficient throughput to test multiple compounds at multiple concentrations in a single plate.” As such, it can be a vital tool for drug discovery.
PREDICT96-ALI is part of an integrated portfolio of technologies and resources at Draper intended to support the drug discovery and national security mission. Some of these capabilities include biothreat detection technologies developed for IARPA’s Finding Engineering-Linked Indicators (FELIX), DARPA’s Detect It with Gene Editing Technologies (DIGET) and BARDA’s Project NextGen: Next Generation Medical Countermeasures.
Authors include Landys Lopez Quezada, Felix Mba Medie, Rebeccah J. Luu, Robert B. Gaibler, Elizabeth P. Gabriel, Logan D. Rubio, Thomas J. Mulhern, Elizabeth E. Marr, Jeffrey T. Borenstein, Christine R. Fisher and Ashley L. Gard.
Released November 14, 2024
