NDA Grant 2020 report: novel treatments for Darier disease
Philip Curman
Karolinska Institutet, Department of Medicine, Solna, Dermatology Division, and Karolinska University Hospital, Dermato-Venereology Clinic, Stockholm, Sweden

Darier disease (DD) is a severe form of blistering anomaly of the skin typified by warty papules, plaques and a foul odour arising from them; it affects 1 in 30 000-50 000 individuals. DD is caused by mutations in the ATP2A2 gene that encodes for the sarco/endo-plasmic reticulum calcium ATPase (SERCA2). SERCA2 maintains endoplasmic reticulum (ER) calcium homeostasis, which is critical for proper cellular function. SERCA2 dysfunction in DD was previously shown to cause ER stress, a cellular process that may lead to cell death and compromised ER function. Today, severe DD is treated with oral retinoids, though most patients discontinue the treatment in the long term due to side effects. Also, this treatment does not target the disease mechanism. Thus, no satisfactory treatment for DD exists.

We have established several functioning keratinocyte models for DD and have begun testing drugs with the potential of directly targeting the disease mechanism of DD. Several laboratory techniques including live cell confocal microscopy imaging, cell survival assays, Western blotting, RT-qPCR, siRNA knock-down techniques, dispase mechanical dissociation assay, SERCA mutant proteins etc. are used. The project is still ongoing, and results thus far looks promising. The results have also been instrumental in receiving a grant from The Swedish Research Council (Vetenskapsrådet, VR) for an investigator-initiated clinical trial that is planned to start shortly.

The 2020 NDA grant aided in the process by providing time in the lab to do the necessary background work to create the functioning cellular models for the evaluation of targeted treatments for DD. We hope that the results will ultimately lead to new, effective treatments for this group of patients.