Efficacy of a Metalloproteinase Inhibitor in Spinal Cord Injured Dogs

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.

Acute Spinal Cord Injury

“…Recent reviews presenting novel neuroprotective drugs 4,6 and currently tested molecules in dogs include: (1) polyethylene glycol (compared with methylprednisolone sodium succinate in a phase III study, North Carolina State University), which was previously tested against historical controls 89 ; (2) glial growth factor 2 (North Carolina State University) in a phase I study; and (3) matrix metalloproteinase blocker (in a large-scale randomized blinded phase II study, Texas A&M University). 90 Selection of appropriate candidate drugs remains problematic, but it is suggested that the following should be favored in future studies: (1) drugs already in use for other related or unrelated conditions; (2) drugs that can be administered by intravenous infusion or orally; or (3) drugs for which evidence of efficacy persists if given with a delay following injury. 91 What Is the Evidence for Cell Transplantation in the Acute Phase of Spinal Cord Injury?…”

Adaptation of the Basso–Beattie–Bresnahan locomotor rating scale for use in a clinical model of spinal cord injury in dogs

“…To assess concurrent validity, all SCI-affected dogs at each time point were also simultaneously assigned locomotor scores using two previously validated canine scales at each time point: the Olby spinal cord injury scale (OSCIS) (Olby et al, 2001) and the modified Frankel scale (MFS) (Levine et al, 2014). Both raters (SAM and RBS) have extensive experience applying these scoring systems in a veterinary clinical setting.…”

“…Dogs also offer heterogeneity in lesion and patient-related factors that closely approximate the human condition, allowing investigators to quickly and economically conduct large-scale veterinary clinical trials to rigorously test an intervention before they introduce it to humans (Jeffery et al, 2011). While several well-publicized canine treatment trials have been recently completed, quantitative outcome measures to assess recovery in the canine model are currently limited (Granger et al, 2012; Levine et al, 2014). Quantitative locomotor scales are one of the most widely used behavioral outcome measures across species.…”

The chondrodystrophic dog: A clinically relevant intermediate‐sized animal model for the study of intervertebral disc‐associated spinal pain

“…For example, our institution alone manages approximately 200 cases per year of canine IVDD, most of which would be available for enrollment in treatment studies. Several recent large‐scale multicenter placebo controlled randomized veterinary studies have been performed using the canine spontaneous model of IVDD . While these studies focused on neuroprotective strategies aimed at treating the 10%‐15% of dogs with IVD that can develop severe neurologic complications rather than treatments targeted specifically at disc degeneration, they still serve as important proof of concept regarding feasibility of large‐scale studies using this disease model…”