Calcipotriol as a wound healing agent in RDEB

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)