Immune-Secreted Proteases and Chronic Wound Healing

Shen, S. (1,2), Turner, C. (1,2), Russo, V. (1,2), Hiroyasu S. (1,2), Zeglinski M. (1,2),  Granville D.J. (1,2,3)

1 International Collaboration On Repair Discoveries (ICORD) Research Centre, Vancouver, BC, Canada
2 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada 
3 British Columbia Professional Firefighters’ Burn and Wound Healing Research Laboratory, UBC, Vancouver, BC, Canada

Proteolysis is an important, irreversible post-translational modification that is tightly-regulated during each phase of wound healing. Aberrant proteolysis is a key contributor to tissue injury and impaired healing. In the past, much has been placed on matrix metalloproteinases (MMPs) as therapeutic targets for chronic wound healing. However, it is now clear that each of the 23 human MMPs are functionally diverse and exert different physiological roles. In fact, many are now considered to be anti-targets that are essential for the regulation of inflammation and other processes. As such, other proteases may contribute to impaired healing. In this regard, granzymes (granule-secreted enzyme) are a family of immune cell-secreted serine proteases that are abundant in many age-related, chronic inflammatory conditions. Emerging research suggests that granzyme B (GzmB) contributes to tissue injury, inflammation, impaired remodeling, and/or blistering through the cleavage of cell surface receptors, adhesion proteins and/or extracellular matrix proteins. We have recently developed a potent, gel-formulated, topical GzmB inhibitor (VTI-1002) that is currently in pre-clinical evaluation in several animal/human models of skin inflammation and disease. In the present study, VTI-1002 was assessed in a murine burn model. Diabetic mice were subjected to thermal injury and topical VTI-1002 was applied daily for 30 days post-injury. VTI-1002 was well-tolerated with no evidence of toxicity or other adverse events. Topical GzmB inhibition significantly attenuated initial burn wound expansion and accelerated wound closure. Further histology showed a thinner epidermal layer, stronger decorin staining and greater collagen organization in VTI-1002-treated groups compared to the vehicle control group. GzmB inhibitor-treated wounds also exhibited greater tensile strength compared to controls, suggesting that GzmB inhibition improves tissue remodeling. In summary, topical GzmB inhibition represents a novel therapeutic strategy for the treatment of wounds characterized by inflammation and excessive proteolyses.