Researchers will use the technology to identify new drug targets and therapies.
Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University will use funding from the National Institutes of Health (NIH) to develop clinically relevant in vitro models of influenza infection in the human lung based on their human Organ-on-a-Chip (Organ Chip) microfluidic cell culture technology. By modulating the host response to infection in these models, they hope to identify potential new antiviral agents.
NIH’s National Center for Advancing Translational Sciences (NCATS) is funding several projects within its “Tissue Chip for Disease Modeling and Efficacy Testing” initiative, which is focused on investigating human microphysiological systems as potential facilitators of drug development. The hope is that by developing effective human models, the success rate for drug candidates in clinical trials can be raised above the current level, which is lower than 40%. The Wyss project is one of 13 receiving approximately $15 million over two years.
An effective human model is needed for the development of drugs to treat influenza because animal models do not reflect the mechanism used by viruses to infect humans. The Wyss researchers will use lung Small Airway and Alveolus Chip devices lined with living human lung cells which have been previously shown to reproduce normal lung physiology and lung diseases, including chronic obstructive pulmonary disease (COPD), asthma and pulmonary edema.
The size of computer memory sticks, the Lung Chips each consist of two < 1-millimeter-wide parallel hollow channels that are separated by a porous membrane, on each side of which appropriate cells are cultured (lung alveolar or airway epithelial cells on one side in one channel and lung capillary endothelial cells on the opposite side of the same membrane in the second channel in order to mimic the tissue-tissue interface found within these lung regions. Air is passed through the channels with lung epithelial cells and growth medium through the “vascular channels,” allowing manipulation and study of the engineered organs for extended periods (weeks to months).
The two types of chips will first be linked together to allow virus infections to follow their natural course – infection of small airway cells followed by infection of the lung alveoli, leading to tissue break down and edema. The researchers will then link the two Lung Chips to a human Liver Chip in order to study how antiviral drugs are chemically converted to active metabolites in the liver. Using integrated multi-omic analysis and bioinformatics approaches, they will assess genome-wide changes in gene expression and alterations in the synthesis of proteins and metabolites that result from infection in the different lung Organ Chips with the goal of identifying key changes in the host response to viral infections that may be targeted to develop new anti-influenza drugs.
“Virtually all existing antiviral drugs target the virus itself, however, the ability to study influenza infection in human Lung Chips also allows us to study the host response to infection in a highly controlled way,” said principal Investigator and Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences. “We hope to leverage this new capability to develop a new class of anti-influenza drugs that effectively make the lung tissues resistant to viral infection.”