calcipotriene and Epidermolysis-Bullosa

Epidermolysis bullosa (EB) is the umbrella term for a group of rare inherited skin fragility disorders caused by mutations in at least 20 different genes. There is no cure for any of the subtypes of EB resulting from different mutations, and current therapy only focuses on the management of wounds and pain. Novel effective therapeutic approaches are therefore urgently required. Strategies include gene-, protein- and cell-based therapies. This review discusses molecular procedures currently under investigation at the EB House Austria, a designated Centre of Expertise implemented in the European Reference Network for Rare and Undiagnosed Skin Diseases. Current clinical research activities at the EB House Austria include newly developed candidate substances that have emerged out of our translational research initiatives as well as already commercially available medications that are applied in off-licensed indications. Squamous cell carcinoma is the major cause of death in severe forms of EB. We are evaluating immunotherapy using an anti-PD1 monoclonal antibody as a palliative treatment option for locally advanced or metastatic squamous cell carcinoma of the skin unresponsive to previous systemic therapy. In addition, we are evaluating topical calcipotriol and topical diacerein as potential agents to improve the healing of skin wounds in EBS patients. Finally, the review will highlight the recent advancements of gene therapy development for EB.

Topics: Anthraquinones; Antibodies, Monoclonal, Humanized; Antimicrobial Cationic Peptides; Antineoplastic Agents, Immunological; Calcitriol; Carcinoma, Squamous Cell; Cathelicidins; Clinical Trials, Phase II as Topic; Epidermolysis Bullosa; Genetic Predisposition to Disease; Genetic Therapy; Humans; Immunotherapy; Immunotherapy, Active; Molecular Targeted Therapy; Multicenter Studies as Topic; Nivolumab; Palliative Care; Programmed Cell Death 1 Receptor; Prospective Studies; Research; Skin Neoplasms; Therapies, Investigational; Wound Healing

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.

Topics: Aged; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Antineoplastic Agents; Calcitriol; Cathelicidins; Cell Line; Cells, Cultured; Dermatologic Agents; Epidermolysis Bullosa; Humans; Keratinocytes; Male; Wound Healing