One milligram of VX, a nerve agent, can kill a person. Imagine the devastating effects of a large amount of weaponized VX released in the air over a large crowd. The Defense Threat Reduction Agency’s Joint Science and Technology Office is working to lessen the repercussions of this type of attack by finding new ways to protect warfighters against a broad spectrum of chemicals that cross the blood brain barrier (BBB).
JSTO’s Dr. Brian Pate is leading the department’s basic research on warfighter recovery products and capabilities by formulating approaches to counter threats that affect the central nervous system. Developing this ‘brain rescue’ will provide the capability to protect against and treat neurological insults resulting from exposure to organophosphate chemicals or threat agents.
Organophosphate pesticides such as paraoxon, and nerve agents including tabun, sarin, soman and VX, induce damage to the BBB — a protective cellular layer that prevents foreign materials from entering the brain. DTRA’s multifaceted initiative uses innovative approaches to explain transport mechanisms across the BBB with the goal of understanding effects and designing improved in vitro and in silico models. Outcomes from this research will aid in developing new entries into the BBB to increase warfighter protection against alpha viruses and nerve agents. The program will also improve the ability to analyze risk and protect warfighters from a range of neuro-damaging infectious diseases and toxicants.
Currently, most medical countermeasures are prevented from crossing the anatomical BBB because they lack the characteristics to transverse this layer (i.e. receptor specificity, lipophilicity, polarity, etc.). Research teams at Johns Hopkins University, Sheba Medical Center, Columbia University and the University of Pittsburgh are collaborating to overcome these challenges.
The Johns Hopkins University team is using a multidisciplinary approach to focus on the transport of potential neurotoxicant antidotes across the BBB.In addition, a new strategy to transport oximes into the central nervous system is also under consideration. The team has engineered a unique set of state-of-the-art tools, including a novel artificial microvessel platform (see figure), a focused two-photon confocal microscopic in vivo imaging technique, and a mouse model to use in understanding relevant pathways within the brain. This provides a unique capability that assesses the influence of nerve agent simulants on the structure and function of the BBB.
A complementary effort at Sheba Medical Center investigates paraxon-induced BBB dysfunction via a triple arm mechanism exploring the cellular systems involved in transport, while examining possible countermeasures to reverse deleterious effects such as cell death that occurs post-exposure to nerve agents. The use of a magnetic resonance imaging has the benefit of scanning the entire central nervous system and is capable of longitudinal rather than the Johns Hopkins two-photon, high resolution imaging. Combining these two methodologies, using the low resolution scanning to identify the area of interest in the exposed neurological tissue samples followed by the high-resolution technique, gives micro and macro views of both structure and function following nerve agent insults, as well as how the BBB looks with medical countermeasures pretreatment.
Columbia University is also commencing work on a new broad based approach to isolate aptamers that stabilize acetylcholinesterase so that a nerve agent adduct will be unable to bind irreversibly to nerve agents. These aptamers will be used in transport mechanistic and structural studies to develop small molecule therapeutics capable of protecting acetylcholinesterase and enabling its reactivation.
In addition, a new effort at the University of Pittsburgh focuses on understanding the short and long term in vitro and in vivo effects post nerve agent exposure. This work examines novel oxime compounds and
antioxidants that may be capable of crossing into the central nervous system to more effectively reduce acute and chronic toxicity of nerve agents as compared to current drugs.
From broad-based approaches to focused efforts, these concurrent endeavors aim to enable medical countermeasures to transverse the BBB to protect against agents (short term); apply mechanistic control and transport existing drugs across the BBB that previously lacked central nervous system access (mid-term). These approaches demonstrate a proof of concept, which may be used in future research for medical countermeasure development.
The result of this program will provide a new generation of neurological rescue methods to protect warfighters exposed to chemical agents, in addition to building a more capable force prepared for emerging threats.
|Date Posted:||04.17.2017 15:06|
|Location:||FORT BELVOIR, VA, US|
This work, Brain Rescue: Recovery From Neurological Attack, is free of known copyright restrictions under U.S. copyright law.