FORT DETRICK, Md. – Researchers at the Defense Health Agency Research & Development-Medical Research and Development Command’s Medical Research Institute of Chemical Defense have developed a new model for testing nerve agent exposure and drug efficacy that more accurately replicates human responses to toxic substances. The model, developed with funding from the Joint Science and Technology Office for Chemical and Biological Defense, Chemical and Biological Technologies Department, Research and Development Directorate, Defense Threat Reduction Agency (JSTO CBDP, RD-DTRA), is already being used in studies that could lead to the fielding of the next generation of nerve agent countermeasures – ensuring improved Warfighter survivability, resiliency, and lethality in chemically contaminated environments.
The new testing method, developed by research chemist Dr. C. Linn Cadieux and her team at USAMRICD's Medical Toxicology Research Division, makes it possible to conduct precise “apples-to-apples” comparisons of different countermeasures to assess their efficacy more precisely than before.
“This method provides decisionmakers with an easy to understand comparison table that can be used to identify how well a given countermeasure works against a given nerve agent,” says Cadieux. “That kind of information is very helpful for making decisions about which new countermeasures to field.”
Nerve agents work by interfering with the electrical signals that cause muscles to contract and relax. In a healthy nervous system, an enzyme called acetylcholinesterase – or AChE for short –modulates these electrical signals. Nerve agents prevent AChE from carrying out that vital function, causing muscles to remain paralyzed – potentially causing permanent injury to vital organs and, in severe cases, death through asphyxiation or cardiac arrest.
The model developed by Cadieux with fellow research chemists Dr. Nicholas Paparoidamis and Dr. Robert diTargiani, uses human AChE to mimic how a healthy person responds to nerve agent exposure and life-saving medical treatments more accurately than other laboratory models currently in use. It promises to allow researchers to screen candidate drugs much more quickly than currently possible, potentially speeding up the process of fielding new lifesaving countermeasures to protect Warfighters.
DISTRIBUTION STATEMENT A. Approved for Public Release
In addition to providing protection against nerve agents, the new model also shows promise in aiding in the development of therapies for other neurodegenerative disorders in which AChE plays a role, including Alzheimer’s disease and dementia. In part because of her work on this project, Cadieux received a 2024 Presidential Early Career Award for Scientists and Engineers. Administered by the National Science and Technology Council, PECASE is the federal government's highest honor for outstanding early career scientists and engineers.
DTRA approached Cadieux to undertake the study in 2020 as a follow-on to a previous successful study that her team had conducted for JSTO. While the COVID pandemic – which began shortly after the project started – required the team to scale back the level of international participation that had originally been envisioned, the team was still able to incorporate feedback from the international partners and keep the momentum going. They also collaborated closely with researchers throughout multiple offices within USAMRICD, drawing on their expertise to ensure the work adhered to the rigorous standards of the Good Laboratory Practice regulatory framework, which will be crucial if the drugs are submitted to the U.S. Food and Drug Administration for review. As a result, the team was able to successfully evaluate the effectiveness of four different nerve agent countermeasures using the new model.
JSTO plans to incorporate the results of the study into its predictive tool for chemical and biological operational health effects called FXCODA. This tool will use the data to estimate potential human health impacts resulting from nerve agent incidents over time. This information will, in turn, inform the selection of the next generation of medical countermeasures.
Cadieux says the contributions of Paparoidamis and diTargiani and their teams to the success of the project are an example of how USAMRICD’s culture of encouraging collaboration and innovation leads to game-changing outcomes.
“This project allowed me to work with a great team that took my crazy idea and brought it all the way to fruition and create something that will help save Warfighters’ lives,” Cadieux said. “It also makes us very happy to know how useful this work is going to be across so many different fields. That’s why we do what we do.”