Development of epoxy-tiglianes as novel small molecule therapeutics for impaired re-epithelialisation associated with non-healing, chronic skin wounds in the aged

Normal (acute) dermal wound healing occurs through a series of phases, to induce wound closure and restore skin barrier function.

However, non-healing chronic wounds, such as venous and diabetic ulcers, represent an important source of morbidity in ageing societies and are a significant economic burden to Healthcare Providers worldwide. Indeed, chronic wounds are estimated to affect ~2-3% of the UK population, costing the NHS ~£4.5-5.1BN/p.a. [1].

These cause significant pain and disability, dramatically affecting patient quality of life [2]; with projections estimating further escalations in their prevalence as age demographics and type II diabetes rates increase worldwide [3-5].

Due to disruptions in skin barrier integrity, chronic wounds are commonly characterised by bacterial colonisation/infection, contributing to perpetual inflammation and altered keratinocyte/fibroblast repair capabilities, culminating in impaired wound re-epithelialisation and closure [6-7].

Despite many chronic wound treatment modalities being available, these often offer limited benefit to healing outcomes and consequently, non-healing or recurrence remain common.

Thus, there remains a significantly unmet clinical need for more efficacious therapies, capable of restoring normal healing responses in chronic wounds [8].

Epoxy-tiglianes are a novel class of diterpene esters isolated from native Australian rainforest plant, Fontainea picrosperma.

Prototype epoxy-tigliane, EBC-46 (tigilanol tiglate), possesses potent anti-cancer properties, mediated via protein kinase C (PKC) activation [9]; and is currently under clinical development as a human/veterinary anti-cancer drug for cutaneous and subcutaneous tumours.

EBC-46 also stimulates exceptional dermal wound healing in vivo post-tumour destruction, particularly manifested as accelerated wound re-epithelialisation and closure, 1-month post-treatment [10-11].

These studies provide compelling proof-of-concept data supporting further assessment of epoxy-tiglianes as therapeutics for other clinical situations associated with impaired re-epithelialisation, such as chronic wounds. We have previously confirmed that EBC-46 and analogues (e.g.

EBC-211, EBC-1013) stimulate significant proliferation and migration by human immortalised keratinocytes (HaCaTs) in vitro, mediated via PKC activation and differential keratin, cell cycle/proliferation, migratory, differentiation, proteinase and cytokine/chemokine gene expression.

Patents relating to this work are filed and manuscript submitted (Biochemical Pharmacology; see supplementary Figures, Appendix I).

We will now undertake complementary studies to confirm epoxy-tigliane (EBC-46, EBC-1013) wound healing responses in primary human keratinocytes, more representative of in vivo epithelial repair.

As veterinary studies have only provided qualitative macroscopic confirmation of wound healing efficacy to date, we also aim to obtain quantitative macroscopic/microscopic histological data on topically-applied, epoxy-tigliane efficacies in promoting wound re-epithelialisation and other key healing parameters, using the established in vivo (db/db mouse) impaired wound healing model.