Of Mice and Human

Courtesy Photo | A DNA technician, with the Armed Forces Medical Examiner System DoD DNA Operations, prepares DNA for extraction. Photo courtesy of the U.S. Army. Photo by Sgt. Sarah D. Williams.  

FORT BELVOIR, VA, UNITED STATES

06.15.2020

Courtesy Story

Defense Threat Reduction Agency's Chemical and Biological Technologies Department

The use of mice and other small animals, referred to as animal models, is common in early phases of drug development and other biomedical research. The benefits of using the mouse as an animal model are many, but important differences between human beings and mouse models impede the translation of results generated from experiments on mice to inform medical breakthroughs in humans. An approach to overcoming the differences between mouse models and humans is to genetically modify mice, i.e., alter specific genes of mice so that they are more human-like or ‘humanized.’

In this way, and through support from the Defense Threat Reduction Agency’s Chemical and Biological Technologies Department, researchers at the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD) created a new humanized mouse strain that is capable of more accurately predicting both the human response to nerve agent exposures and the effectiveness of medical countermeasures used to treat nerve agent exposures. Because of this new mouse model, critical drug development knowledge will be gained faster and earlier than it is currently, which will enable researchers to focus on developing medical countermeasures most likely to save warfighters’ lives.

Mice are selected as animal models in early drug development and biomedical research because they are physiologically similar to humans, easy to care for, engage in a rapid reproductive cycle, and are less expensive than larger animal models. While these characteristics of mice make them attractive animal models for researchers to study human disease and to predict human responses to hazardous chemicals, there are differences between mice and humans that hinder or delay the direct transfer of information gleaned from mouse models to predicting human responses in the real world. Until recently, there were two enzymatic obstacles to using the mouse as a model to predict human responses to nerve agent exposures. First, mice have the protein carboxylesterase circulating in their blood, but humans do not. Second, while both humans and mice have the acetylcholinesterase (AChE) enzyme, the shape of the enzyme differs between them.

Carboxylesterase and AChE are both enzymes that interact with nerve agents, so any difference in the enzymes between humans and mice can cause a difference in how the two animals physically respond to nerve agent exposure. When a mouse is exposed to a nerve agent, its carboxylesterase acts as a scavenger to reduce the physiological toxicity of the nerve agent.¹ For example, the lethal dose of soman (also known as GD), a synthetic nerve agent, is 10- to 20-times lower for a human than a mouse due to the protection provided by the circulating carboxylesterase in the mouse. If a mouse did not have this protein, then the toxicity a mouse would experience from a nerve agent exposure would be more similar to a human’s experience. To make mice more humanized, a team of scientists, in 2011, genetically modified a strain of mice by ‘knocking out’ or inactivating the circulating carboxylesterase gene.²

Mice and humans both have AChE, which is a protein in the family of cholinesterase enzymes that contributes to the functioning of the nervous system. For example, AChE is involved in neurotransmission, which is the process of the brain telling muscles when to move. A nerve agent inhibits the function of AChE, which can lead to seizures and other symptoms, including death. AChE’s structure differs slightly among different animals, including mice and humans; the differing structure affects how well the enzyme responds to therapeutic treatments against nerve agents. Variations across species are concerning because data from these animal models are being used to predict the effectiveness of new therapeutics in humans. To eliminate the structural variation in AChE between the mouse and human, USAMRICD scientists further genetically modified the carboxylesterase knock-out mice by ‘knocking in’ or adding the gene that encodes the human form of AChE. USAMRICD researchers named the new mouse KIKO (pronounced keekoe) for the human AChE enzyme knocked in (KI) and the circulating carboxylesterase enzyme knocked out (KO).

Scientists at USAMRICD evaluated the KIKO mouse model for how it responds to nerve agents. Compared to unmodified mice, KIKO mice survived exposure to nerve agents at rates more similar to humans. In 2019, academic and industrial researchers around the world learned about the KIKO mouse model at the 3rd International Conference CBRNE — Research & Innovation in Nantes, France. The KIKO mouse model has been well received by academic and industrial researchers working in chemical defense.

The KIKO mouse model is a new cost-effective testing platform to study nerve agents and their medical countermeasures, allowing scientists to predict, early in drug development research, the human response to nerve agents and other chemicals affecting the nervous system. The significant improvement in predicting human physiological response helps screen out ineffective medical countermeasures earlier in the biomedical research cycle, which results in an earlier use of resources and animal test subjects focused toward the most promising drug candidates that will effectively protect the warfighter against nerve agents.

^1. Sterri SH, Fonnum F. 2015. The role of carboxylesterases in therapeutic intervention of nerve gases poisoning. In Handbook of Toxicology of Chemical Warfare Agents. Academic Press; 1099–1106.
^2. Duysen EG, Koentgen F, Williams GR, et al. 2011. Production of ES1 plasma carboxylesterase knockout mice for toxicity studies. Chemical Research in Toxicology. 24(11):1891–8.

POC: Brian Reinhardt, [e-mail]

• Date Taken: 06.15.2020
• Date Posted: 06.16.2020 11:42
• Story ID: 372219
• Location: FORT BELVOIR, VA, US