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.