We propose to use our immature large animal models of traumatic brain injury (TBI) to accelerate basic science therapeutic discoveries to clinical trials for TBI in children. Because mitochondria play a key role in many primary and secondary pathologic pathways in TBI, we will use cyclosporin A (CsA) to rescue mitochondrial function, reduce cell death and improve neurofunction. Due to its safety profile in humans, pleiotropic effects, and success in multiple preclinical adult rodent TBI models, CsA (CsA) has exciting potential as a therapy for pediatric TBI. Because CsA is also off-patent and already in use in children for other indications, the results of the proposed preclinical therapy development plan can be translated rapidly to clinical trial. We determine the optimal dose of CsA for the spectrum of moderate TBI in the child, using our established immature porcine TBI models: focal lesions from controlled cortical impact and diffuse brain injury from rapid nonimpact head rotation. In addition, we include optimization at 1 hr after TBI to determine dosing strategies in the field, and at 6 hrs after TBI for hospital-based strategies. To enhance translation, we include clinically relevant physiological monitoring and current critical care management strategies. Furthermore, we use both histological and neurofunctional endpoints to identify agents that reduce brain injury acutely, and have sustained cognitive benefits.
In Aim 1, we will evaluate short-term dose response using short term terminal outcomes. For each start time and injury type, the most effective and the lowest dose with significant effect will continue to Aim 2.
In Aim 2 we test these dosing strategies for efficacy in neurocognitive outcomes, measured 6 days after injury, to identify the optimal dosing strategy to evaluate in pediatric TBI clinical trials.
In Aim 3 we will identify sex-specific cognitive recovery and toxicology responses to the optimal dose of CsA.
In Aim 4 we design the clinical trial from the porcine data and published human studies, and submit an IND application to the FDA. This state-of-the-art, innovative preclinical study design can be applied to future evaluations of other therapies longer treatment windows, other ages, other brain injuries, and to other agents that promote neurorecovery or repair.
Traumatic brain injury (TBI) is the leading cause of death and acquired disability in childhood in the US. Despite the alarmingly high incidence, there are no specific treatments for TBI in children. We will use our immature large animal models of TBI with fidelity to children to create a new translational bridge between basic science discoveries in the rodent to pediatric clinical trials for TBI.
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|Atlan, Lorre S; Smith, Colin; Margulies, Susan S (2018) Improved prediction of direction-dependent, acute axonal injury in piglets. J Neurosci Res 96:536-544|
|Pasquesi, Stephanie A; Margulies, Susan S (2017) Failure and Fatigue Properties of Immature Human and Porcine Parasagittal Bridging Veins. Ann Biomed Eng 45:1877-1889|
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