TRAnslational Therapeutics based on Mechanisms of pathophysiology and regeneration in traumatic brain injury and multiple sclerosis
The brain is arguably our highest priority for efforts to promote repair and recovery after injury or disease. Our brains use white matter tracts as information superhighways that rapidly transmit signals to connect networks of neurons to enable movement, sensation, learning, emotion, and so much more. These electrochemical signals are carried along axons that are wrapped by myelin, which makes signal transmission more efficient, and provides protection and trophic factors. Damage to axons, and/or their myelin sheaths, occurs from many forms of insults that can cause loss of function to the axons and desynchronize signals of the broader neuronal networks resulting in diverse symptoms.
There are currently no available treatments that can protect against axon or myelin damage and promote recovery of axon function to prevent long term symptoms and neurodegeneration. Our research team is working to identify therapeutic targets and test treatments to protect against axon damage and enhance myelin repair. We focus on this combination of axon and myelin effects that need to be addressed together to restore axon function in many neurologic disorders. We have conducted in-depth characterization of the white matter damage in mouse models of two major neurologic disorders, multiple sclerosis and traumatic brain injury.
Our therapeutics studies leverage an array of techniques from mechanistic approaches at the molecular and cellular level through to brain imaging and blood biomarkers that translate well to clinically used diagnostic measures. Our recent findings have leveraged mouse genetics as a “proof-of-concept” that demonstrated axon and myelin protection from genetic inactivation of the SARM1 protein, which executes a molecular pathway of axon degeneration after traumatic injury. These results show promise for developing brain-penetrant small molecules to inhibit SARM1 as a novel drug treatment for patients with traumatic brain injury. A second strategy to develop new treatments is to repurpose existing drugs, rather than developing novel ones, which can dramatically accelerate translation to use in patients. We conducted preclinical trials of repurposing of 4-aminopyridine (active ingredient in dalfampridine) as an acute therapy after experimental traumatic brain injury and found remarkable beneficial effects on axon and myelin pathology. We continue to explore these candidate therapeutic pathways while also continuing to develop both techniques for analysis of the treatments and strategies for screening and advancing the most promising results to inform effective future clinical trials.