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Calcipotriol as a wound healing agent in RDEB

Completed
Project leadDr. Christina Guttmann-Gruber and Dr. Josefina Piñón Hofbauer
Organisation EB House Austria
Project budgetEUR 12.500,00 (PMU) and DEBRA Austria core funding to the EB House Austria
Start date / Duration01. Sep 2011 / 72 months
Funder(s) / Co-Funder(s) PMU, DEBRA Austria
Research area Symptom prevention & relief

Project details

Short lay summary

Recessive dystrophic epidermolysis bullosa (RDEB) patients suffer from chronic and repeatedly infected wounds, which predisposes them to the development of aggressive and life-threatening skin cancer in these areas. Vitamin D3 (VD3), the sunshine vitamin, is an often neglected but critical factor for proper skin function, underscored by the fact that intact skin possesses the entire machinery required to produce active VD3. Active VD3 enables the skin to respond to wounding and infection by enhancing antimicrobial defenses and initiating repair processes. These findings are relevant in the context of RDEB, as limited sun exposure due to wound dressings and reduced outdoor activity of patients could lead to a local vitamin D3 deficiency in the skin. Thus, enhancing active VD3 levels at sites of injury could be beneficial to wound healing and control of infections in RDEB patients.

Scientific summary

The skin serves as the primary source of VD3 for the entire body. While other tissues and organs rely on renal and hepatic hydroxylation steps to obtain active VD3 via the circulation, skin keratinocytes possess the entire enzymatic machinery required to produce calcitriol, the active form of VD3. Calcitriol is a potent ligand for the vitamin D receptor (VDR), and this complex modulates the expression of genes involved in skin homeostasis and wound healing. In the case of the latter, a notable target gene is the antimicrobial peptide cathelicidin (CAMP), whose active form LL-37, exhibits direct antimicrobial activity, modulates innate and adaptive immune responses, and promotes re-epithelialization of healing skin. This research group demonstrated that CAMP levels were significantly reduced in a subset of RDEB keratinocyte lines compared to non-EB keratinocytes which may in part account for deficient wound healing observed in patients. Notably CAMP levels could be restored by treatment with a low concentration of the active VD3 analog calcipotriol. Reduced scratch closure in RDEB cell monolayers could be enhanced up to 2-fold by calcipotriol treatment, and the secretome of calcipotriol-treated cells additionally showed increased antimicrobial activity. Furthermore, 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 to improve wound healing in RDEB patients. This was successfully demonstrated in a single-patient observation study, wherein closure of a long-standing wound was achieved within 2 weeks of treatment with a low-dose topical formulation, accompanied by resolution of pathogenic Staphylococcus aureus infection, and reduction of itch and pain.

Strategic relevance

  • DEBRA strategic goal: Symptom prevention and relief
  • Project goal: To determine the appropriate treatment dose for calcipotriol and provide sufficient pre-clinical evidence to support a clinical trial in EB patients
  • Preceding/ follow-on projects, and related projects: A double-blind, placebo-controlled cross-over study to assess the efficacy of topical calcipotriol (Psorcutan®-ointment containing 0.05 µg/g calcipotriol) to improve wound healing in dystrophic epidermolysis bullosa (DEB) (CALCIDEB2016, Eudranet 2016-001967-35)

What did this project achieve?

In the context of the emerging evidence in the field of the role of microbial infections in the early onset of skin cancer in RDEB, this project highlights both the anti-microbial and anti-neoplastic effects of calcipotriol, supporting its use as a vital therapeutic option in this high-risk patient subgroup.

Topical application of a low-dose formulation of calcipotriol, achieved rapid and complete closure of a chronic DEB wound, an improvement of local microbiome diversity, and a reduction in itch and pain, in a single-patient observation study. The known safety profile of calcipotriol facilitates a rapid repurposing for off-target use in DEB.

Based on the positive pre-clinical data obtained in this project, the EB House Austria initiated a Phase 2, placebo-controlled trial (CALCIDEB2016 Eudranet 2016-001967-35) to assess the efficacy of a low-dose calcipotriol ointment in wound healing in DEB.


Keywords

Wound healing
Vitamin D
Antimicrobial
Antineoplastic
Microbiome
Itch and pain
Single-patient observation study
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