Development of mechanism-based Lysyl oxidase inhibitors to reduce skin fibrosis and scarring

Ms Nutan  Chaudhari1, Dr.  Andrew Stevenson1, Ms. Priyanka Toshniwal1, Dr.  Wolfgang  Jarolimek2, Professor Fiona  Wood1, Dr. Mark Fear1

1Burn Injury Research Unit, University Of Western Australia, Crawley, Australia, 2Pharmaxis, 20 Rodborough Road, Frenchs Forest, Australia

Abstract:

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.

References
De Roche R, Lüscher N, Debrunner H, et al. (1994) Epidemiological data and costs of burn injuries in workers in Switzerland: an argument for immediate treatment in burn centres. Burns 20: 58-60.
Hong H-H, Uzel MI, Duan C, et al. (1999) Regulation of lysyl oxidase, collagen, and connective tissue growth factor by TGF-beta1 and detection in human gingiva. Lab Invest 79: 1655-1667.
Loeser JD and Melzack R. (1999) Pain: an overview. The Lancet 353: 1607-1609.
Penn JW, Grobbelaar AO and Rolfe KJ. (2012) The role of the TGF-β family in wound healing, burns and scarring: a review. International journal of burns and trauma 2: 18.


Biography:

Andrew Stevenson is a junior postdoc working at the Burn Injury Research Unit at the University of Western Australia. He was awarded his PhD in 2016 titled “Investigating the role of epigenetics in scar maintenance” from UWA, and has been lucky to continue on this and other research focused on the mechanisms and treatment of fibrosis at the Burn Injury Research Unit.