Matrix Metalloproteinases as a Therapeutic Target to Improve Neurologic Recovery after Spinal Cord Injury
Annual rept. 30 Sep 2011-29 Sep 2012
CALIFORNIA UNIV SAN FRANCISCO
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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. Scope These studies have focused on efficacy of GM6001 in the context of optimal therapeutic window and dependency on injury severity, using clinically relevant outcome measures that include neurologic assessments and assays of bladder function. Major findings -Developed reproducible models of graded spinal cord injuries in the mouse. -Spinal cord injury in mice resulted in marked injury severity-dependent changes in bladder function including the emergence of uninhibited bladder contractions, increased bladder volumeweight, and increased urinary retention. -Conducted the first blinded, randomized study to assess efficacy of GM6001 when delivered 8 hours after a moderate spinal cord injury in mice. Though group sizes were small, these data show promising benefit of GM6001 in terms of neurologic improvement and decreased abnormal bladder contractility relative to vehicle controls. -Completed pharmacokinetic study of GM6001 in 10 dogs. The study supports the rapid development of maximal plasma concentration after subcutaneous delivery, the presence of plasma drug levels capable of inhibiting MMPs in vitro, and 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. -Completed normal dog cystometry in 10 dogs -Enrolled 6 dogs with acute intervertebral disk herniation-associated spinal cord injury into serial cystometry study.
- Anatomy and Physiology
- Medicine and Medical Research