Efficacy of a metalloproteinase inhibitor in spinal cord injured dogs.
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.
Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
Jonathan M
JM
Levine
Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
Noah D
ND
Cohen
Department of Bioengineering, University of California San Diego, San Diego, California, United States of America.
Michael
M
Heller
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
Virginia R
VR
Fajt
Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
Gwendolyn J
GJ
Levine
Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
Sharon C
SC
Kerwin
Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Alpa A
AA
Trivedi
Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Thomas M
TM
Fandel
Department of Anatomy, University of California San Francisco, San Francisco, California, United States of America.
Zena
Z
Werb
Department of Bioengineering, University of California San Diego, San Diego, California, United States of America.
Augusta
A
Modestino
Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America; Department of Physical Therapy and Rehabilitation, University of California San Francisco, San Francisco, California, United States of America.
Linda J
LJ
Noble-Haeusslein
D000818:Animals; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage; D004151:Dipeptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004283:Dog Diseases / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004285:Dogs; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects; D007405:Intervertebral Disc Displacement / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000662:veterinary*; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D020782:Matrix Metalloproteinases / Q000097:blood; D013119:Spinal Cord Injuries / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000662:veterinary*
D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D020782:Matrix Metalloproteinases; D004121:Dimethyl Sulfoxide