Topical small molecule granzyme B inhibitor improves remodeling in a murine model of impaired burn wound healing

Abstract

Granzyme B (GzmB) is a serine protease that has long been thought to function exclusively in lymphocyte-mediated apoptosis. In recent years, this paradigm has been revisited due to the recognition that GzmB accumulates in the extracellular milieu in many autoimmune and chronic inflammatory disorders, and contributes to impaired tissue remodeling due to the cleavage of extracellular matrix proteins. Knockout studies suggest that GzmB-mediated cleavage of decorin (DCN) contributes to impaired collagen fibrillogenesis and remodeling. As DCN is anti-fibrotic and contributes to reduced hypertrophic scarring, GzmB-induced DCN cleavage could play a role in wound healing following burn injury. In the present study, a novel, gel-formulated, first-in-class small-molecule inhibitor of GzmB, VTI-1002, was assessed in a murine model of impaired, diabetic burn wound healing. VTI-1002 exhibited high specificity, potency, and target selectivity. Gel-formulated VTI-1002 was able to penetrate the stratum corneum and was retained in the skin with minimal systemic absorption. Daily topical administration of VTI-1002 gel for 30 days following thermal injury showed significantly accelerated wound closure, increased DCN protein levels, and collagen organization that was translated into significantly increased wound tensile strength compared to controls. Overall, VTI-1002 gel was well-tolerated in vivo and no adverse events were observed. Topical application of VTI-1002 represents a novel therapeutic approach for the treatment of cutaneous burn wounds.

The Small Molecule NLRP3 Inflammasome Inhibitor MCC950 Does Not Alter Wound Healing in Obese Mice

“…C57Bl/6J mice were treated topically with MCC950 [1 mg/dose] in 30% pluronic gel, daily from D0 to D4 post-wounding, based on previous studies using small molecule inhibitors topically [ 12 , 13 ]. No significant difference in wound surface was found between MCC950 and gel alone (control) groups ( Figure 1 a,b).…”

Proteases in Pemphigoid Diseases

“…Through these cleavages and degradations in the extracellular spaces, GzmB is expected to regulate inflammation, cell adhesion, cell migration, anoikis, coagulation, fibrinolysis, and cell-cell adhesion. Present at low levels in healthy tissue, GzmB is elevated in numerous pathological conditions such as atherosclerosis, rheumatoid arthritis, transplant rejection, acute graft vs. host disease, discoid lupus, drug eruption, atopic dermatitis, impaired burn wound, and photoaging (279, 289–297). In these diseases, pathological contributions of GzmB are suggested through not only intracellular apoptotic function but also extracellular proteolytic role.…”

“…Recently, a topical GzmB inhibitor was tested on impaired burn wound murine model, however, there are currently no clinically-approved GzmB inhibitors on the market (289).…”

A Virus-Derived Immune Modulating Serpin Accelerates Wound Closure with Improved Collagen Remodeling

“…As highly potent inhibitors of the serine proteases in these cascades, SERPINs also play a role in regulating wound healing [28,29]. Therapeutically, some groups have reported that application of recombinant SERPINSs (Alpha-1-antitrypsin, SERPINA1; anti-chymotrypsin, SERPINA3N) and related small molecules can promote wound healing [30,31,32,33,34].…”