PI: Neal Simon

Co-PI: Shi-fang Lu 

University: Lehigh University

Industry partner: Azevan Pharmaceuticals 

Traumatic brain injuries are the world’s leading neurological disorder with 56+ million cases annually. Mild TBIs (mTBI; concussions) account for 90% of these injuries and result from causes including falls, car accidents, and sports participation. mTBIs can be single or repetitive (rmTBI). While the effects were thought to rapidly resolve, we now know that they can result in post-concussion syndrome (PCS) in ~50% of cases. PCS impacts cognitive function, causes depression, inappropriate aggression, anxiety, and/or PTSD, and increases the long-term risk of neurodegenerative disease. These neuropsychiatric symptoms pose a significant public health problem and there are no approved treatments for PCS. 

A major challenge is that mTBI is frequently underreported--patients present for care only after PCS symptoms become chronic, making therapeutic strategies that are effective beyond the acute injury window urgently needed. We have demonstrated that treatment with CNS-penetrant vasopressin 1a receptor (V1aR) antagonists mitigates injury-related deficits in preclinical mTBI models when administered shortly after injury. Notably, this drug class also is efficacious across behavioral domains central to PCS, including aggression, depression, anxiety, and PTSD, supporting its translational relevance for patients with PCS.

We propose to continue advancing the translational development of CNS-active V1aR antagonists using a computer-controlled momentum exchange model of repeated mTBI in rats. The candidate compound, AVN849, demonstrated efficacy in initial assays that tested for circadian rhythm restoration and cognition. In this continuation project, it will be assessed in additional models applicable to PCS, including affective, additional cognitive, and immunochemical experiments that will comprehensively characterize the ability of the drugs to significantly reduce or eliminate biomarkers of post-concussion syndrome. 

Successful completion of these studies will generate clinically relevant data to support advancement of V1aR antagonists toward human trials, establishing a novel therapeutic strategy for neuropsychiatric symptoms following mTBIs.