Clinic‐ready inhibitor of MMP‐9/‐12 restores sensory and functional decline in rodent models of spinal cord injury

Abstract

Dear Editor, This study demonstrated that short-term inhibition of matrix metalloprotease (MMP)-9 and MMP-12 in both mouse and rat models of spinal cord injury (SCI) using the clinic-ready, orally bioavailable and specific inhibitor, AZD1236, attenuated injury-induced oedema, proinflam-matory pain markers, pain sensation and blood-spinal cord barrier (BSCB) breakdown. Inhibition of MMP-9 and MMP-12 also protected against SCI-induced sensory and locomotor deficits. By demonstrating these unprecedented improvements with a clinic-ready MMP inhibitor, using a dosing regimen, which is anticipated to be safe and well tolerated in SCI patients, we are now well-placed to move swiftly into a Phase 2a study in patients. After a dorsal column (DC) SCI in mice, 1 MMP-9 (Figure 1A) and MMP-12 (Figure 1B) mRNA peaked at 1 and 5 days, respectively. Protein levels (Figure 1C,D) and enzyme activity (Figure 1E,F) in the spinal cord mirrored their mRNA levels. MMP-9 and MMP-12 activity were significantly suppressed in serum and cerebrospinal fluid (CSF) (Figure 1G,H) after oral (Figure 1G,H,K) and intrathecal (Figure 1I-K) delivery of AZD1236, as well as in the spinal cord itself (Figure 1L,M). After DC injury, water content of the spinal cord peaks at 3 days (Figure S1); however, oral and intrathe-cal delivery of AZD1236, twice daily for 3 days, caused a dose-dependent reduction in SCI-induced water content , with intrathecal delivery requiring much lower doses (5 mg/kg vs. 200 mg/kg) (Figure 2A,B), and inhibition of both MMP-9 and MMP-12 was required to fully halt SCI-induced oedema (Figure 2C). In comparison to pre-optimised tool and clinical grade experimental MMP inhibitors (Figure S2A-I and Table S1), AZD1236 was significantly more effective at attenuating SCI-induced water content (Figure S2J). SCI-induced pain develops in two thirds of patients, 2 through increased proinflammatory pain cytokines such as interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. and interkeukin-6 (IL-6) 3 (Figure 2D,E), which were all significantly attenuated by AZD1236 (Figure 2D,E). In a severe clip compression (CC) model of SCI where neu-ropathic pain develops, 4 commensurate attenuation of spinal cord water content by AZD1236, (Figure S3A), MMP-9/MMP-12 enzyme activity (Figure S3B)…