Unmet Need
Traumatic brain injury (TBI) is regarded as one of the major causes of death and disability in the United States, contributing to 30% of all injury-related deaths. Over 150 people die daily from consequences of a TBI and those that survive often face difficulties and disabilities that can last for the duration of their lives. TBIs range in severity and result from a bump, blow, or jolt to the head that interrupts normal neurological functioning. One common TBI neuropathology is traumatic axonal injury (TAI), which is characterized by impaired axoplasmic transports, axonal swelling, and disconnection. TAI can seriously hinder neurologic function and is often a cause of death in TBI. At present, there are no treatments for TBI and TAI along with other neurodegenerative diseases and it can be difficult to study and model these pathologies in vivo. Consequently, there is a critical unmet need to develop new ways to prevent and treat TAI using in vivo modeling and novel high-resolution neuroanatomical tools in order to improve the outcomes and prognosis for TBIs.
Technology Overview
Johns Hopkins researchers developed an in vivo mouse model in which they induced TAI in the head of mice and then visualized the brain stem and cervical spinal cord using CLARITY to achieve single axon-resolution. Use of these novel neuroanatomical tools to generate a 3D structure of the corticospinal tract at single-axon resolution allowed for an improved qualitative and quantitative understanding of the neuropathology of TAI, which is thought to be the initiation of a cascade of a series of metabolic events ultimately resulting in axonal degeneration and disconnection. The researchers found that TAI results from dysfunction of the axon destruction protein signal, SARM1. Pharmacologically inhibiting or deleting SARM1 in mice completely prevented TAI and lead to robust axonal protection.
Stage of Development
The inventors have identified a key regulator and modulator in an axon death pathway that can be manipulated to protect axons from degeneration before they commit to this pathway, which is the hallmark of TAI. Thus, this regulator represents a potentially novel therapeutic target for preventing and treating TAI and TBI. Their novel in vivo modeling and 3D reconstructive system can also be used to identify other new molecular targets for drug development for axonal protection.
Publications
Ziogas NK, et al. The Journal of Neuroscience 38(16), 4031-4047, 2018
Neurobiology of Disease 171 (2022) 105808 - https://doi.org/10.1016/j.nbd.2022.105808
