Skin scars are disfiguring and debilitating and cause a large economic burden to society(De Roche et al., 1994). In addition to the loss of function and aesthetic issues, scars can also lead to psychological problems and pain (Loeser and Melzack, 1999). However, to date there are no approved treatments available and very few in development.
Scarring is a multi-factorial fibrotic process which ultimately results in excessive collagen accumulation with concomitant poor appearance and pliability(Penn et al., 2012). The lysyl oxidase (LOX) family of enzymes has a major role in the formation of cross-links in collagen and elastin. This cross-linking leads to decreased solubility and increased stability of collagen, exacerbating collagen accumulation(Hong et al., 1999). This makes LOX a potentially attractive target for anti-fibrotic drug development.
In this study, we have shown that fibroblasts isolated from patients with skin fibrotic disorders (Dupuytren’s disease and Keloid scarring) have increased expression of the LOX family members (LOX and LOXLL1) which results in highly cross-linked extracellular matrix. Novel small molecule mechanism-based LOX and LOXL1 inhibitors have been developed for topical applications. These inhibitors reduce cross-linking and normalise appearance of extracellular matrix in vitro. The inhibitors also improve scar appearance and repair in small animal and porcine injury models. The data suggests that these inhibitors may provide an effective therapeutic strategy for scarring and skin fibrosis.