LB986 Novel glycopeptide potential in keloid formation prevention and recurrence

Abstract

During excessive scar formation, when keloid scars arise, a dysfunction of the underlying regulatory mechanisms leads to chronic inflammation, excessive collagen synthesis or deficient matrix degradation and remodeling. Keloids are characterized by fibroblasts with excessive deposition of extracellular matrix (ECM) components, showing increased type I/III collagen ratio and elastin expression. Initial experiments in fibroblasts suggest KEL-01 has keloid prevention properties. First, the effect of KEL-01, a novel glycopeptide, was evaluated on a gene panel in human normal fibroblasts (NF). In-vitro gene screening was done on NF treated with 50 mg/ml of KEL-01. Gene levels relative to the control were quantified for those involved in ECM synthesis, ECM degradation, and oxidative stress. Second, KEL-01’s role on the production of proteins, specifically collagen I, III, and matrix metalloproteinase (MMP) 1 and 3 expression, was analyzed in NF and keloid fibroblast (KF) cultures. Here, KEL-01 was added to NF and KF cultures at 5mg/ml for 48h. Levels of collagen I and III were quantified. In NF gene expression, KEL-01 downregulated genes involved in ECM synthesis, collagen I, III and elastin, while it upregulated genes involved in ECM degradation, namely MMP1 and 3. KEL-01 also upregulated superoxide dismutase 2 in NF. In protein expression studies, collagen I levels were higher in KF controls than in NF, while collagen III levels, MMP1 and 3 were significantly lower in KF control relative to NF. However, the addition of KEL-01 significantly decreased the levels of collagen I and collagen III in KF while having no effect on MMP1 and 3. When KEL-01 was added to the KF, the ratio of collagen I/III was regulated to that of NF. An additional assay done showed Nrf2 pathway activation via KEL-01, which is down-regulated in keloids. KEL-01 gene and protein expression studies show the potential for keloid prevention by avoiding ECM deposits and reducing the type I/III collagen ratio. Further development including formulation, dosage and clinical trials are needed.