Matrix Metalloproteinases as a Therapeutic Target to Improve Neurologic Recovery After Spinal Cord Injury

Abstract : Purpose: We are evaluating efficacy of GM6001, a matrix metalloproteinase (MMP) inhibitor in a murine model of spinal cord injury (UCSF) and in dogs (Texas A & M, TAMU) that sustain naturally occurring spinal cord injuries resulting from spontaneous intervertebral disk herniation (IVDH). Scope: These studies focus on efficacy of GM6001 in the context of an optimal therapeutic window and dependency on injury severity, using clinically relevant neurologic and urologic outcome measures. Major findings: -Spinal cord injury (SCI) in mice resulted in marked injury severity-dependent changes in locomotor and bladder function. - GM6001 has an extended therapeutic window. When given up to at least 8 hours post injury, GM6001 resulted in injury severity dependent efficacy in a murine model of SCI. GM6001 treatment resulted in both neurologic and urologic benefit after a moderate level of SCI and was associated with a decrease in lesion volume and greater spared white matter volume. In contrast, GM6001 did not rescue locomotor or bladder function in mice with severe SCIs. - Pharmacokinetic study of GM6001 in 10 dogs supports the short-term safety of the drug. Plasma drug levels following a single dose are sustained at a significant level likely to result in MMP inhibition for approximately 72 hours, which support a single dose strategy in the clinical trial. -Developed cystometry protocol on 10 uninjured dogs. -Enrolled 17 dogs with acute IVDH-associated SCI into serial cystometry study. Dogs with SCI that are nonambulatory lack normal voiding reflex, have larger bladder capacity, elevated post-cystometry baseline pressure, and larger residual volume compared to measures taken during recovery. Significance: We have found that GM6001 is efficacious when the therapeutic window is extended up to at least 8 hours after SCI of moderate severity. However, a similar benefit is not seen after a more severe SCI.