4-Aminopyridine Promotes Extensive Recovery in Acute Spinal Cord Injury
Abstract
There is no current way to treat acute traumatic spinal cord injury (SCI) so as to reliably restore significant function and decrease tissue damage. We have discovered that a currently available, US Food and Drug Administration (FDA)-approved, drug (4-aminopyridine, or 4AP) has the previously unknown effects of promoting extensive and durable behavioral recovery and decreasing tissue damage when applied acutely in models of traumatic SCI and other problems (i.e., peripheral nerve injury, muscle atrophy) relevant to individuals with SCI. We therefore want to repurpose 4AP for the treatment of SCI. The rationale for this proposal comes from our discoveries that transient treatment with 4AP at clinically relevant dosages causes a durable recovery of function that exceeds that of any pharmacological agent that has thus far been thought of sufficient promise to transition from the laboratory to clinical studies. Our proposed interventions align with the therapeutic focus on development, validation, and timing of promising interventions to address consequences of SCI and to improve recovery as 4AP treatment provides a potential means of addressing the critical questions of how to promote functional recovery and how to decrease tissue damage. The military benefit of this proposal is the potential to effectively treat SCI with an inexpensive medical intervention suitable for rapid development. Moreover, because we found that initiation of 4AP treatment 24 hours after injury outperforms other reported pharmacological interventions, which have the additional challenge of needing to be applied more quickly to yield benefit, implementation of 4AP treatment in an injury-appropriate time period is more feasible than is the case for other potential pharmacological treatments for SCI. Moreover, the ease of 4AP administration means treatment could even be initiated on or near the battlefield. The impact of this work is centered on the opportunity to provide an effective treatment for SCI that can be moved efficiently to approval by the FDA to initiate clinical trials at a fraction of the time and cost normally required for new treatments. Thus, this proposal has the potential to lead to the use of 4AP as a defined product for Soldiers with otherwise devastating injuries to the spinal cord. Can 4AP be repurposed to help our Soldiers on the battlefield and in post-injury care? We propose to answer this important question. This proposal is divided into three main aims geared towards answering three critical questions needed to safely allow the analysis of 4AP in patients with SCI. First, we will define optimal therapeutic regimens, including analysis of effects of dosage, timing of treatment initiation and length of treatment duration, and use of bolus or continuous administration in a model of thoracic contusion SCI. As it is unlikely that the first treatment regimen is implemented will be the most effective one, it is important to determine the range of time over which treatment can be initiated, how long treatment should be continued, and whether benefits are increased still further by altering dosage. Thus, our first aim will tell us how best to apply 4AP to individuals with thoracic SCI. At the same time, we will extend our analyses to cervical SCI to confirm that the principles determined in our studies thus far apply equally when the injury is in a different region of the spinal cord. Aim 3 then will confirm confirmation of the safety of 4AP treatment even in instances in which an individual has both SCI and traumatic brain injury (TBI). While observations thus far raise the possibility that it is actually more likely that 4AP treatment will also be beneficial for TBI treatment, it is important to examine this question directly. We have initiated clinical trials of 4AP based on our current data for treating injury to peripheral nerves, and our data on SCI is as promising as that leading to FDA approval of an
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710331
Entities
People
- Mark Noble
Organizations
- United States Army
- University of Rochester