Low-dose calcipotriol can elicit wound closure, anti-microbial, and anti-neoplastic effects in epidermolysis bullosa keratinocytes

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) patients suffer from chronic and repeatedly infected wounds predisposing them to the development of aggressive and life-threatening skin cancer in these areas. Vitamin D3 is an often neglected but critical factor for wound healing. Intact skin possesses the entire enzymatic machinery required to produce active 1-alpha,25-dihydroxyvitamin D3 (calcitriol), underscoring its significance to proper skin function. Injury enhances calcitriol production, inducing the expression of calcitriol target genes including the antimicrobial peptide cathelicidin (hCAP18), an essential component of the innate immune system and an important wound healing factor. We found significantly reduced hCAP18 expression in a subset of RDEB keratinocytes which could be restored by calcipotriol treatment. Reduced scratch closure in RDEB cell monolayers was enhanced up to 2-fold by calcipotriol treatment, and the secretome of calcipotriol-treated cells additionally showed increased antimicrobial activity. Calcipotriol exhibited anti-neoplastic effects, suppressing the clonogenicity and proliferation of RDEB tumor cells. The combined wound healing, anti-microbial, and anti-neoplastic effects indicate that calcipotriol may represent a vital therapeutic option for RDEB patients which we could demonstrate in a single-patient observation study.

Epidermolysis bullosa: Advances in research and treatment

“…Our preliminary data on hCAP18 mRNA levels in skin tissue samples taken from RDEB patients and RDEB patient‐derived keratinocyte cell lines support this hypothesis . We also observed an increase in hCAP18 expression at transcript and protein level in RDEB keratinocytes by treatment with distinct concentrations of the active vitamin D3 analogue, calcipotriol, which is already used routinely in the clinical treatment of psoriasis .…”

“…Our preliminary data on hCAP18 mRNA levels in skin tissue samples taken from RDEB patients and RDEB patient‐derived keratinocyte cell lines support this hypothesis . We also observed an increase in hCAP18 expression at transcript and protein level in RDEB keratinocytes by treatment with distinct concentrations of the active vitamin D3 analogue, calcipotriol, which is already used routinely in the clinical treatment of psoriasis . This correlated with reduced colony formation upon incubation of E coli with supernatants from cultured calcipotriol‐treated RDEB cells compared to controls while retaining any anti‐proliferative effect of calcipotriol detrimental to wound healing …”

“…Based on our results including a promising single‐patient observation study, we are currently investigating the potential of improved wound healing in dystrophic EB via increased in vivo expression of cathelicidin and thus enhanced antimicrobial defense by topical administration of calcipotriol in a double‐blind, placebo‐controlled crossover study (EudraCT‐No 2016‐001967‐35). Notably, locally produced cathelicidin can serve as a chemoattractant for innate immune cells including neutrophils, which produce and store vast amounts of AMPs and release them at sites of infection, underlining the utility of this approach in diseases characterized by increased susceptibility to bacterial infections.…”

Small molecule drug development for rare genodermatoses – evaluation of the current status in epidermolysis bullosa

“…While in localized EB variants inflammatory aberrations mainly affect the micromilieu of lesional skin (leading to tissue remodeling [4][5][6][7]), a systemic impact was shown in severe subtypes such as RDEB, in which extensive cutaneous involvement is associated with a systemic inflammatory response and chronification of inflammatory cascades that contribute to the systemic morbidity of EB [8][9][10][11][12]. Against this background, the induction of inflammatory traits defines new therapeutic targets including skin barrier restoration, infection control/surveillance, immune response/modulation, anti-neoplastic interference and interference with epigenetic drivers of the disease.…”

ÖGDV Preisträger stellen sich vor: Der Wissenschaftspreis der ÖGDV 2018 ging an Dr. Christina Guttmann‐Gruber und Dr. Beate Lichtenberger

“…In unserer von der ÖGDV prämierten Forschungsarbeit (Abbildung ) „Low‐dose calcipotriol can elicit wound healing, anti‐neoplastic, anti‐microbial, and anti‐neoplastic effects in epidermolysis bullosa keratinocytes“ untersuchten wir die Eigenschaften des ­Vitamin D3‐Analogs Calcipotriol auf die Wundheilung bei RDEB. Vitamin D3 kann mit Hilfe von Sonnenlicht direkt in Keratinozyten der Haut gebildet werden und ist für eine effektive Gewebereparatur von entscheidender Bedeutung.…”