Preclinical Development of Intranasal IGF-1 Therapy for TBI

Traumatic brain injuries (TBIs), even those classified as mild or moderate severity, often result in persistent deficits in cognitive functions such as learning and memory. The hippocampus, critical to these functions, is highly vulnerable to traumatic insults but has the capacity to generate new neurons throughout adulthood. The inability to sufficiently compensate for trauma-induced hippocampal neuron damage through endogenous neurogenesis is thought to limit cognitive recovery. Thus, strategies to protect hippocampal neurons from death or to stimulate neurogenesis-related hippocampal plasticity hold promise for the amelioration of TBI-related cognitive dysfunction. Using a transgenic mouse model, we have shown that astrocyte-driven overexpression of insulin-like growth factor-1 (IGF-1) significantly attenuates the loss of mature neurons, increases recovery of the immature hippocampal neuron population, supports long-term survival of posttrauma-born neurons, and improves cognition in brain-injured mice. We now propose to translate these exciting basic research findings to a clinically relevant treatment approach by optimizing parameters for intranasal delivery of recombinant human IGF-1 and establishing the functional efficacy of IGF-1 treatment for both contusion (moderate to severe) and concussive (mild) brain injuries. We have preliminary data to demonstrate that intranasal IGF-1 administration significantly enhances the recovery of immature hippocampal neurons after controlled cortical impact brain injury. In Aim 1, the dose and frequency of IGF-1 administration will be varied to determine the maximal neurogenic benefit as assessed through recovery of immature hippocampal neuron population as well as the protection of mature neurons. The therapeutic window for intranasal IGF-1 delivery will be determined for both the neurogenic and neuroprotective responses. The optimized delivery paradigm will be utilized in Aim 2, which will examine the ability of IGF-1 to sustain long-term survival and appropriate location and morphology of posttrauma-born neurons and improve hippocampal-mediated learning and memory function in a model of contusion brain injury. To expand the potential clinical utility of intranasal IGF-1, in Aim 3 the ability of IGF-1 treatment to promote hippocampal neurogenesis and improve cognitive function after repeated mild TBI will be evaluated. Procedures for ensuring experimental rigor, including assessment of males and females, randomization and blinding, replication studies and adequate statistical power and analyses, are incorporated throughout the design. No studies to date have tested the ability of intranasally delivered IGF-1 to ameliorate the effects of TBI. The proposed research will provide compelling evidence for (a) the neurogenic and neuroprotective potential of a clinically relevant and highly translatable IGF-1 delivery paradigm, (b) evidence-based guidelines for optimized intranasal dosing parameters for TBI, and (c) data to support the broad therapeutic utility of IGF-1 therapy across diffuse and focal brain injury phenotypes.