Defining Novel Druggable Pathways in Darier, Hailey-Hailey, and Grover Disease: From Bedside to Bench and Back

Dr. Cory Simpson presented information about his research identifying novel therapeutic targets for rare skin blistering disorders, including Darier, Hailey-Hailey, and Grover disease.  

Cory Simpson, MD/PhD, is an associate professor in the Department of Dermatology at the University of Washington. He created Simpson Lab in 2021.

First, Simpson described the clinical features, pathology, and genetics of Darier and Hailey-Hailey disease. Both diseases are autosomal dominant with adolescent onset. They may present with flaccid blisters, crusted erosions, and fissured plaques caused by the loss of adhesion between keratinocytes in the epidermis. Cutaneous infections are common due to impaired tissue differentiation and loss of skin barrier function. 

Darier disease is caused by mutations in the ATP2A2 gene, which encodes the sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2), while Hailey-Hailey disease is caused by mutations in the ATP2C1 gene, which encodes the secretory pathway calcium ATPase type 1 (SPCA1).  Although the genetic causes of Darier and Hailey-Hailey disease were identified more than 25 years ago, no treatments are FDA approved. Interestingly, the pathology of these inherited disorders overlaps with Grover disease, an acquired skin blistering disorder of unknown origin, suggesting all three might share a common root cause.

Second, Simpson discussed his laboratory research identifying MEK, an activator of the mitogen-activated protein kinase (MAPK) signaling pathway, as a potential therapeutic target for Darier, Hailey-Hailey, and Grover disease. He used CRISPR/Cas9 gene editing to produce human keratinocytes deficient in SERCA2 or SPCA1, replicating the genetics of Darier and Hailey-Hailey disease. Keratinocytes lacking SERCA2 replicated the key pathologic features of Darier disease, including reduced intercellular adhesion and impaired differentiation; keratinocytes without SPCA1 similarly had weakened cell-cell adhesion and in Hailey-Hailey disease.

RNA sequencing and proteomics of SERCA2-deficient keratinocytes revealed overactivation of MAPK signaling that could be dampened by MEK inhibition. In his lab’s models of Darier, Hailey-Hailey, and Grover disease, Simpson showed that several MEK inhibitors that are already in clinical use were able to restore cell-cell adhesion. Based on this work the MEK1/2 inhibitor trametinib, which is FDA-approved for melanoma, was used successfully in a case report of a patient with severe Darier disease. 

Simpson concluded by emphasizing the need for ongoing basic science research to advance dermatology. He hopes his findings will translate into novel therapies for patients with these rare skin diseases by repurposing FDA-approved drugs.

Mark your calendar: The DF Clinical Symposium returns January 27–31, 2027.