Developing an Acute Traumatic Brain Injury Therapy to Protect Axons and Prevent White Matter Neurodegeneration

No available treatments protect the brain from the effects of traumatic brain injury (TBI) incurred during military training or combat exposures. The consequences of TBI present critical resiliency and readiness issues when service members suffer cognitive and emotional symptoms. For the Military Health System, the broad scope of TBI presents challenges to providing effective clinical care in deployed and training environments. While advances in protective gear and procedures continue to be a high priority, head injuries will still continue to occur and cause immediate physical damage to brain tissue, such as shearing of axons. Importantly, the majority of axon damage is not caused by immediate mechanical breakage at the time of head injury. The initial injury triggers physiological and immunological cascades that cause damage to additional axons, which continue to enter a degenerative process in the following weeks. This time interval opens a therapeutic window to intervene with treatments to protect axons. Our studies in animal models of TBI have revealed novel therapeutic targets, which develop with distinct timing post-injury, and shown promising results of a candidate treatment.

Our current results demonstrate that 4-aminopyridine (4-AP) is a promising candidate drug that is already in clinical use for chronic neurological disease and could be rapidly repurposed for early treatment in TBI as a new clinical indication. TBI treatments to protect or repair damage cells and tissues, which have failed to date, have not focused on axon damage in the context of white matter injury. Long axons that form white matter tracts of the brain are highly vulnerable to damage from the forces to the head during TBI. White matter tracts act as highways for information flow from one brain region to another. TBI treatments that protect axons and white matter tracts can prevent the dysfunction of brain circuits that results in prolonged symptoms.

We identified remarkable protection of axons with early treatment using 4-AP in a mouse TBI model. Clinically, 4-AP (dalfampridine or Ampyra) is approved as extended release pills to treat walking disability in chronic multiple sclerosis patients. 4-AP therapy is expected to act by enhancing the function of damaged axons, although the specific mode of benefit in multiple sclerosis patients is not known. Our studies revealed similar slowed function and pathology along damaged axons after TBI as occurs with multiple sclerosis. Therefore, we hypothesize that treatment with 4-AP early after TBI will maintain activity in brain circuits to prevent white matter damage and degeneration and, importantly, to ameliorate symptoms.

The proposed studies are expected to provide critical evidence in TBI models to support further studies toward FDA approval for TBI as a new clinical indication for 4-AP therapy. These preclinical studies in rodent models take advantage of the high conservation of molecular and cellular processes of axon and white matter structure and function from rodents to humans. The four proposed objectives will rigorously test the effectiveness of 4-AP acute therapy using translational outcome measures and will screen for adverse effects so that this preclinical data can inform future clinical trials. The experiments will be implemented using best practices for translational research to increase the value of this 4-AP preclinical evidence for predicting success in trials with TBI patients. The results are expected to answer the following critical questions:

• Does 4-AP acute therapy result in long-term benefits after experimental TBI?

• Can internal replication studies, utilizing the highest resolution techniques for white matter pathology validate a robust, reproducible, and durable benefit of acute 4-AP therapy?

• Does acute TBI increase the potential risk associated with 4-AP treatment?

• Can an independent laboratory validate key findings of 4-AP acute therapy in a second TBI model and using another species?

Our proposed studies are critical steps toward advancing this treatment for TBI to provide early protection of brain cells and prevent late-stage neurodegeneration. Early protection is needed to maintain performance and to stay in the fight while deployed. Long-term prevention of neurodegeneration is needed to improve functional outcomes, which will allow military TBI patients to recover, continue to serve, and experience their best possible quality of life. Successful outcomes in the proposed studies will open an opportunity to develop the first protective treatment for TBI to reduce tissue damage and reduce disability from persistent symptoms.