Repurposing diacerein for the treatment of chronic wounds in recessive-dystrophic epidermolysis bullosa patients by modulating matrix metalloproteinase-9 expression.

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in COL7A1, leading to loss or dysfunction of type-VII collagen (C7), a protein essential for skin stability. Clinically, patients suffer from severe skin blistering, chronic or recurrent wounds, and scarring, which predispose to early onset of aggressive squamous cell carcinoma. Previous studies showed that RDEB-keratinocytes (RDEB-KC) express high levels of matrix-metalloproteinase 9 (MMP-9), a molecule known to play a crucial role in wound chronification if dysregulated. We investigated the potential of diacerein, a small molecule that interferes with the MMP-9 regulatory pathway, to improve wound healing in a 5-year old RDEB patient presenting with chronic, generalized skin involvement unresponsive to previous treatment approaches. Upon 4 weeks of topical therapy applied to the patient's back, parents reported a nearly complete wound closure and a significant increase in quality of life. We also provide evidence that diacerein treatment of patient keratinocytes results in a downregulation of MMP-9 expression, accompanied by a reduction in their ability to degrade a fibrinogen matrix. These data characterize diacerein as a potential candidate for improving wound healing in RDEB through its impact on inflammatory as well as epithelial cells.