Abstract
Matrix metalloproteinase-9 is elevated within the acutely injured murine spinal cord and blockade of this early proteolytic activity with GM6001, a broad-spectrum matrix metalloproteinase inhibitor, results in improved recovery after spinal cord injury. As matrix metalloproteinase-9 is likewise acutely elevated in dogs with naturally occurring spinal cord injuries, we evaluated efficacy of GM6001 solubilized in dimethyl sulfoxide in this second species. Safety and pharmacokinetic studies were conducted in naïve dogs. After confirming safety, subsequent pharmacokinetic analyses demonstrated that a 100 mg/kg subcutaneous dose of GM6001 resulted in plasma concentrations that peaked shortly after administration and were sustained for at least 4 days at levels that produced robust in vitro inhibition of matrix metalloproteinase-9. A randomized, blinded, placebo-controlled study was then conducted to assess efficacy of GM6001 given within 48 hours of spinal cord injury. Dogs were enrolled in 3 groups: GM6001 dissolved in dimethyl sulfoxide (n = 35), dimethyl sulfoxide (n = 37), or saline (n = 41). Matrix metalloproteinase activity was increased in the serum of injured dogs and GM6001 reduced this serum protease activity compared to the other two groups. To assess recovery, dogs were a priori stratified into a severely injured group and a mild-to-moderate injured group, using a Modified Frankel Scale. The Texas Spinal Cord Injury Score was then used to assess long-term motor/sensory function. In dogs with severe spinal cord injuries, those treated with saline had a mean motor score of 2 (95% CI 0–4.0) that was significantly (P<0.05; generalized linear model) less than the estimated mean motor score for dogs receiving dimethyl sulfoxide (mean, 5; 95% CI 2.0–8.0) or GM6001 (mean, 5; 95% CI 2.0–8.0). As there was no independent effect of GM6001, we attribute improved neurological outcomes to dimethyl sulfoxide, a pleotropic agent that may target diverse secondary pathogenic events that emerge in the acutely injured cord.
Highlights
Matrix metalloproteinases (MMPs) are endopeptidases that degrade the extracellular matrix [1]
Guidelines for the conduct of spinal cord injury (SCI) trials developed by the International Campaign for Cures of Spinal Cord Injury Paralysis were utilized to assist with the design of a randomized, doubleblinded, placebo-controlled canine trial including inclusion/exclusion criteria, randomization protocol, data handling, and the a priori definition of outcome metrics and statistical approaches.[22]
In the dog receiving 300 mg/kg GM6001 twice daily for 3 days, sites of subcutaneous drug deposition were surrounded by a connective tissue capsule with minimal inflammation; there was mild bile duct hyperplasia
Summary
Matrix metalloproteinases (MMPs) are endopeptidases that degrade the extracellular matrix [1]. Several members of the MMP family, including MMP-9 (gelatinase B) and MMP-12, have been implicated in early secondary pathogenesis after spinal cord injury (SCI) [2,3,4] These MMPs are released by local cells as well as by infiltrating leukocytes and result in reduced cell-cell adhesion, disruption of the blood-spinal cord barrier, up-regulation of pro-inflammatory cytokines, and demyelination [1,4,5]. While there are local sources of MMP-9, including glia and endothelial cells, neutrophil depletion studies confirm that these leukocytes are the major source of MMP-9 in the acutely injured cord [7] As this protease is not complexed with tissue inhibitor of MMP-1, degranulation of neutrophils results in release of activated MMP-9 [9], which may disrupt the barrier and facilitate transmigration of leukocytes into the injured spinal cord. Broad inhibitors of MMPs may offer greater benefit than specific inhibitors of these proteases
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