Simpson Lab Research Leads to Real-World Treatment

simpson lab members speak Nationally about their Research on Rare Skin Blistering Disorders

The Simpson Lab, headed by Cory Simpson, MD, PhD, FAAD, UW Assistant Professor of Dermatology, recently returned from a whirlwind tour showcasing their research on rare skin blistering disorders at the Society for Investigative Dermatology (SID) annual meeting in Chicago. UW Dermatology PhD students, Jessica Ayers and Karina Schmidt, were both invited to give platform presentations on their work to build new models of Hailey-Hailey disease and epidermolysis bullosa. Dr. Simpson, himself, was invited to speak at the Epidermal Differentiation Disorders (EDD) Symposium.

The international gathering brought together scientists, clinicians, patient advocates, industry representatives, and NIH/NIAMS leaders who are aiming to finally move the needle for patients with rare skin disorders that lack effective therapies. Participants shared ideas, tools, and strategies covering the full range of research from laboratory models to clinical trials with the goal of building synergy among multiple rare skin disease communities.

The symposium was organized by the Pachyonychia Congenita (PC) Project, Decoding Darier’s Disease, and the Foundation for Ichthyosis and Related Skin Types (FIRST), which previously supported the Simpson Lab through its Research Grant Program. Dr. Simpson now serves on the FIRST Medical and Scientific Advisory Board, but noted that he was actually introduced to the FIRST community by the late Dr. Phil Fleckman, a long-time UW Dermatology faculty member and physician-scientist who served for decades on the Board of FIRST, which supports patients with EDDs and funds research into these rare diseases.

Dr. Simpson presents his results on genetic skin disease model for Darier disease

At the EDD Symposium, Dr. Simpson was invited to present hot-off-the-presses results from his newest genetic skin disease model that his lab developed in conjunction with a generous donor and close collaborators in the lab of Kathleen Green, PhD at Northwestern University, where Simpson completed his MD and PhD degrees in 2012 and first became interested in rare skin blistering disorders. His latest human tissue model replicated Darier disease, an orphan skin blistering disorder that causes recurrent skin wounds, pain, and infections, yet has no FDA-approved therapy.

Dr. Simpson, who sees patients with Darier disease in a weekly subspecialty clinic at UW dedicated to rare skin blistering disorders, noted that, “Despite knowing its exact cause for over 25 years, there has been no development of a targeted and effective treatment for patients suffering from Darier disease.”

Motivated by his patients and his passion for translating basic science research into novel therapies, the Simpson Lab set out to engineer a new Darier disease “organotypic” model, which produces nickel-sized pieces of skin that are grown in the lab and used to study rare diseases and test out treatments in a pre-clinical setting before involving patients. In collaboration with the Fred Hutch Cancer Center’s Gene Editing Facility, Simpson’s team leveraged the DNA editing system, CRISPR/Cas9, which allows scientists to change the genetic code of skin cells called keratinocytes to insert the “typo” that is known to cause genetic skin diseases in patients.

It was an incredibly exciting day in the lab when their first set of skin cultures looked very much like a skin biopsy from a patient with Darier disease. Now they have a personalized skin model that can be used to test out new therapies with the goal of inspiring eventual clinical trials.

A step further - Simpson lab "borrows" FDA-approved drug to potentially treat rare skin blistering diseases

Toward that goal, Simpson’s lab has published a series of papers that discovered a clever way to borrow a drug that has already been FDA-approved for another disease and potentially use it to treat rare skin blistering diseases.

In a 2023 publication in the journal JCI Insight, Dr. Simpson’s team found that existing drugs targeting an enzyme called MEK, which are primarily used for cancer treatment, helped skin cells stick together more strongly and reduced the blistering seen in his model of Darier disease. The team then extended these results to show that MEK inhibitors also worked in a model of a much more common skin blistering disorder called Grover disease, which looks the same as Darier disease under the microscope.

These papers led Simpson to propose that MEK inhibitors might be re-purposed to treat a variety of skin blistering diseases that he sees in the clinic. Most recently, Simpson Lab member Jessica Ayers found that MEK inhibitors in conjunction with a second drug targeting an enzyme called ROCK, made skin cells resistant to blistering in a model of Hailey-Hailey disease, known as the sister disorder of Darier disease due to their overlapping clinical features and similar gene targets.

Lab research informs treatment for real-world patients

Perhaps most excitingly, Simpson has been ecstatic to see his lab research informing the treatment of real-world patients, which was recently highlighted by UW Medicine Vitals. In two published case reports, patients with severe Darier disease were treated with MEK inhibitors and showed remarkable improvement in their skin.

Though further research is needed to specifically test the safety and efficacy of MEK inhibitors for treating these rare diseases, Simpson is optimistic that his lab’s work may eventually inspire a clinical trial and ultimately an FDA-approved therapy for his patients.

While excited to build on his lab’s momentum and the synergy that is building for these rare diseases, Dr. Simpson acknowledged that,

“Especially at a time of reduced federal grants available from the NIH, support from generous patients, family members, and other donors remains critical to allow us to continue research into these rare skin diseases.”

The UW Department of Dermatology has established a donor fund dedicated to Rare Skin Disorders Research for anyone wishing to support the Simpson Lab’s research.