Journal Article

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

Arns, Steve, Boey, Anthony, Russo, Valerio, Papp, Anthony, Wu, Zhenguo, Liggins, Richard, Granville, David J., Shen, Yue, Turner, Christopher T., Huang, Rachel, Cameron, Dale R., Westendorf, Kathryn, Oram, Cameron, Tan, Jason, Raithatha, Sheetal A., Kopko, Irina, Jaquith, James, Zeglinski, Matthew R., Nabai, Layla, Bozin, Tatjana, Zhao, Hongyan, Hiroyasu, Sho, Zeng, Haishan

2018

Overview

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. Chronic wounds: Gel encourages healing and reduces scarring A promising, recently developed topical treatment prevents detrimental enzyme activity in burn wounds, accelerates healing and reduces scarring. Chronic wounds that do not heal fully and require ongoing medical attention are common in the elderly, obese, and/or diabetic populations, resulting in enormous costs to healthcare services. Recent research indicates that an enzyme called granzyme. (GzmB) accumulates in chronically inflamed wounds, impairing collagen organization and disrupting tissue remodeling. David Granville at the University of British Columbia, Vancouver, Canada, and co-workers trialed a topical gel designed to inhibit GzmB activity in burn injuries in diabetic mice. When applied to the wounds for 30 days, the gel improved wound closure and remodeling while reducing scarring. The gel targeted wounds directly with no effect on surrounding tissues, and no adverse effects were observed during treatment.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
• Subject: 13/51 / 14/69 / 64/110 / 64/60 / 692/308/575 / 692/699/578 / Administration, Topical / Animal models / Animals / Apoptosis / Biomedical and Life Sciences / Biomedicine / Burns - pathology / Cicatrix - pathology / Collagen / Decorin / Diabetes mellitus / Diabetes Mellitus, Experimental - pathology / Disease Models, Animal / Extracellular matrix / Fibrillogenesis / Granzyme B / Granzymes - antagonists & inhibitors / Granzymes - metabolism / Inflammatory diseases / Male / Medical Biochemistry / Mice, Inbred C57BL / Molecular Medicine / Serine / Serine proteinase / Skin / Small Molecule Libraries - administration & dosage / Small Molecule Libraries - pharmacology / Stem Cells / Stratum corneum / Thermal injury / Topical application / Wound healing / Wound Healing - drug effects / 생화학