DARPA to Develop Countermeasures to Prevent Brain Injury to Military Personnel

The U.S. Defense Advanced Research Projects Agency (DARPA)’s Cornerstone program aims to develop safe and effective integrated countermeasures to prevent traumatic brain injury (TBI) to military personnel.

TBIs result in debilitating long-term burden that impacts not only the warfighter but also families, friends and the healthcare infrastructure. Current interventions rely solely on physical protection measures, such as armored vehicles and bulky helmets and treatments are limited to physical and/or psychological rehabilitation protocols with limited success.

When an individual sustains a brain injury, it triggers a complex cascade of events that resemble a domino effect. This starts within milliseconds of exposure with an initial response at the cellular or molecular level, followed by an exponentially expanding set of separate, different, and parallel molecular events that can continue for weeks or months, with each path requiring separate treatment. Cornerstone aims to target the initial response milliseconds after injury, thereby mitigating the need to treat multiple targets simultaneously.

Program proposers are encouraged to combine exposure models (to blast and impact) with emerging neuroscience research tools that have enabled real-time measurement and visualization of molecular and cellular responses in vitro, ex vivo, and in vivo. Methods that allow for the observation of potentially responsive receptors and channels to a variety of energetic stimuli, on the microsecond or millisecond time-scale, would be valuable in validating potential prophylactic countermeasure strategies. Cornerstone performers will successfully pair these highly time-resolved observation capabilities with energetic exposure models as part of a comprehensive countermeasure validation strategy.

“At this time, no treatments for TBI have progressed past Phase II clinical trials because they focus on providing a post-exposure countermeasure,” said Dr. Eric Van Gieson, Cornerstone program manager. “Cornerstone aims to improve mission execution and warfighter protection by reorienting the research community to stop what happens at a molecular level in the first few seconds of exposure to blast or impact. Through this lens, Cornerstone performers will focus on building safe and effective integrated countermeasures--preventing TBI from happening at all.”

The five-year fundamental research effort involves two technical areas (TAs) in three phases aimed at developing preventative countermeasures to TBI. TA1 will identify and validate countermeasures that prevent relevant targets from initiating harmful downstream signaling injury response(s) to a blast (e.g. kinetic) injury. TA2 will develop clinically relevant spatial and temporal delivery of countermeasures that prevent molecular targets from responding to kinetic insult at sites of injury. The goal is that upon program completion, performers will have developed safe, effective integrated countermeasures that allow for repeat prophylactic administration, and provide protection in response to injury. Upon kinetic injury, integrated countermeasures should demonstrate spatial and temporal bioactivity, inhibit the initiation of injury processes, and protect against the development of behavioral and cognitive effects associated with TBI.

Cornerstone performers will have the opportunity to engage with U.S. Government stakeholders, including Department of Defense, as well as appropriate regulatory authorities. Teams also are expected to collaborate with ethical, legal, and societal implications (ELSI) experts.