A study from the University of Washington (UW) indicates that the blistering and recurrent skin infections seen in patients with Darier disease may be reduced by MEK inhibitors. These chemotherapeutic agents are typically prescribed for patients with unresectable or metastatic melanoma.
Although the mutation of the ATP2A2 gene encoding sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) was linked to Darier disease more than two decades ago, the researchers note that no targeted therapies for this disease have been developed. Their study was published in JCI Insight.
“Research into Darier disease has been slowed by the fact that targeting the involved gene in mice does not replicate the skin blistering seen in patients,” said Cory Simpson, MD, PhD of the Simpson Lab at UW in a press release. “Researchers have not had a pre-clinical model, which is essential for testing hypotheses about how the disease works and trying out potential treatments in the lab before involving patients.” The Simpson Lab is affiliated with the UW Division of Dermatology and the UW Medicine Institute for Stem Cell and Regenerative Medicine.
The investigators used gene editing technology to mimic the genetics of Darier disease in 3D human epidermal tissue. When they analyzed the cells with RNA sequencing, proteomics, and confocal microscopy, they found up-regulation of signalling through MEK, which operates in the MAP kinase pathway, a major regulator of cell growth, differentiation, and adhesion. Skin biopsies taken from patients with Darier disease also showed that MEK was hyperactive, suggesting it might be responsible for reducing adhesion among the keratinocytes that cause blistering. The researchers noted that Inhibiting MEK in the keratinocyte model restored cohesion, suggesting that targeting this pathway may be a novel treatment to halt skin blistering in Darier disease.
“We’ve known for more than two decades that Darier disease is caused by mutations in a specific gene, yet we still have no approved treatments to offer patients, which is really frustrating to me as a physician-scientist,” said Dr. Simpson. “Our study is an important step in changing the way we think about treating Darier disease, potentially by repurposing MEK inhibitors that are already available in the clinic.”