Creation of New Chemical Entities (NCEs) for Treating Traumatic Brain Injury
Abstract
Area of Focus Addressed: Treat - Interventions that promote sustained functional recovery, including interventions administered acutely, during the post-acute phase, or during the chronic phase of injury. Background: Between 2000-2021, 444,328 military Service Members have been diagnosed with traumatic brain injury (TBI). It is one of the principal causes of death among Service Members who die within the first hour of wounding. Furthermore, the American public suffer ~1.5mn TBI incidents per annum with around ~15% requiring hospitalization and 1 in 33 die. The financial cost of TBI is estimated at ~$4 billion per year. TBI occurs in two main phases; the primary injury, which is not sensitive to therapeutic intervention, relates to the trauma event that causes mechanical breakdown of brain tissue. Whereas secondary injury, which is sensitive to therapeutic intervention, occurs post trauma and represents the main cause of TBI worsening. Secondary TBI comprises a complex cascade of multiple cellular and molecular events that are associated with increased risk of mortality, neurodegenerative disorders and neurobehavioral deficits. There are no approved TBI treatments. To date, drug development has focused on tackling specific individual secondary TBI events in isolation but have failed to generate positive clinical results. Solution: MicroQuin addresses the lack of TBI treatments through development of small molecule therapeutics that tackle multiple secondary injury events in tandem. Our therapeutics work by targeting a protein called TMBIM6, which is a core regulator of cell stress and survival and shown to be highly neuroprotective. TMIBM6 plays a critical role in progression of all secondary TBI events. In a laboratory setting, our TMBIM6 targeted therapeutics?directly promoted?neuronal cell survival; decreased oxidative stress; positively?regulated cell stress;?inhibited excessive neuron excitement, which can result in cell death; inhibited excessive inflammation; and promoted the injured brain to overcome secondary injury. Animal studies showed TMBIM6 targeted therapeutics can fully remove the secondary injuries caused due to brain injury, even fully reverting a brain injury to a state prior to trauma event. Proposed Project: This project proposes to optimize our therapeutics to improve therapeutic effectiveness, increase the routes of therapeutic administration, and improve drug-like properties. These optimized therapeutics will then be tested in a blast wave animal model to identify a lead drug candidate for progression into human trials. Impact: There are significant number of military (and non-military) TBIs annually, with no treatment options. Typically, the majority (>80%) of TBIs are caused by concussion, sub-concussion, or exposures to explosive blasts, which have minimal primary trauma and progress via secondary TBI events. MicroQuin’s therapeutics are shown to provide considerable protection to secondary TBI events and are stable, lightweight, and easy to handle. This project will significantly enhance the therapeutics and optimize them in a manner so they can be administrated in a battlefield setting and immediately after a TBI event, or as close to it as possible, prior to or during medical evacuation. Furthermore, as TBI has been linked to increased risk of neurodegenerative disorders and neurobehavioral deficits in Veterans, such as the development of Alzheimer’s disease, Parkinson’s disease. In the long-term our products could potentially reduce the likelihood of developing these complex neurogenerative/behavioral disorders. We foresee significant impacts, both immediate and long term, of our therapeutic development to protect Service Members, Veterans and civilians.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311029
Entities
People
- Keith Robinson
Organizations
- United States Army