Novel BDNF-TrkB enhancing therapeutic to treat traumatic brain injury

Traumatic brain injury (TBI) affects an estimated 1.7 million civilians in the US each year at an estimated cost of $76.5 billion in the U.S. alone. Due to the complex nature of the pathophysiological events there remains an unmet medical need for therapeutics that prevent secondary neuronal damage. Brain-derived neurotrophic factor (BDNF) through activation of its high affinity receptor, TrkB, is a key player in promoting learning, and therapeutic strategies to enhance BDNF signaling after TBI facilitate recovery. PSD-95 is a TrkB associated synaptic scaffolding protein required for BDNF-induced signaling. We developed a high affinity and proteolytic stable macrocyclic compound, D-Syn3, targeting the PDZ3 domain of PSD-95. D- Syn3 increases the recruitment of PSD-95 to TrkB to augment pro-survival BDNF signaling. In a series of preclinical studies in TBI rodent models, we found that D-Syn3 rapidly penetrates the CNS to reduce post- injury neuronal death, cis P-tau, gliosis and demyelination, to improve long-term neurobehavioral outcomes. Taking advantage of the distinct pathology in the Controlled Cortical Impact (CCI) and repetitive moderate closed head injury (rmCHI) models, we will fully evaluate the efficacy of our novel BDNF-targeted therapy, which has demonstrated promise in both models. We will determine the efficacy of D-Syn3 to mitigate injury and behavioral deficits using two complementary TBI models: A contusive control cortical impact (CCI) model (Aim 1) and a concussive closed head injury (CHI) model (Aim 2). For each model, we will identify the optimal dosing regimen of D-Syn3 to mitigate pathology. Using this optimal regimen we will evaluate efficacy to prevent impairment in learning/memory, motor function, and depression-like behavior. Given the pilot efficacy of D-Syn3, we anticipate that successful completion of this work will lead to a new therapeutic for TBI. Project Number: 1R21NS147224-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: JOHN MARSHALL (+1 co-PI) | Institution: BROWN UNIVERSITY, PROVIDENCE, RI | Award Amount: $254,400 | Activity Code: R21 | Study Section: Brain Injury and Neurovascular Pathologies Study Section[BINP] View on NIH RePORTER: https://reporter.nih.gov/project-details/11288155