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Simpson uses CRISPR, the gene-editing technology, which can be leveraged for two separate purposes: as a research tool to generate precise DNA alterations in organotypic epidermal cultures to replicate blistering disease; and potentially as a therapy to correct genetic variants in diseased skin.
CRISPR/Cas9 is a fast, cheap, and powerful sequence-specific DNA-modifying technology that tens of thousands of scientists use for research. Clinically, the technology has been approved for use in the biologic Casgevy (exagamglogene autotemcel), which treats sickle cell disease and beta thalassemia by modifying the DNA in a patient’s hematopoietic stem cells. CRISPR has been tested for use in humans to treat cancers, including neuroblastoma, as well as other genetic disorders.
Simpson is replicating pathogenic DNA variants found in blistering disease patients to make personalized organotypic models of the disease. He compares this to a variation of Koch’s postulates for infectious diseases. First, the genetic variation is seen in patients with Darier disease.
When the same DNA change is made using CRISPR, the cell line takes on similar characteristics to the diseased cells of patients. And if the change in DNA is then repaired in the cell line using CRISPR, the cells no longer exhibit the diseased state.
“Organoid skin is accessible and can be scaled in ways you can’t with patients,” Simpson said. “We can make many quarter-sized pieces of skin in the lab and do testing on them versus subjecting patients to whatever we want to test.”
They used CRISPR to mutate ATP2A2 in cultured keratinocytes to create an in vitro simulation of Darier disease (Zaver et al. 2023). Comparative mRNA sequencing demonstrated alterations in the EGF receptor signaling pathway that leads to overactivation of a downstream kinase (ERK) in both the cultured cells and in skin biopsies of patients with Darier disease.
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Dr. Aimee Payne’s Path to Creating CAAR-T Cell Therapies
Aimee S. Payne, MD, PhD received one of three highly competitive DF Stiefel Scholar Research Awards reserved for exceptional mid-career investigators.
They then tested whether the excessive ERK activation could be reduced by inhibiting its upstream kinase, MEK. Multiple MEK inhibitors have already been approved to treat various cancers, including trametinib. Trametinib did, indeed, reverse the diseased state of keratinocytes in their in vitro model, leading to the cells adhering to each other much more strongly.
Knowing a patient’s particular DNA sequence change that causes their Darier disease now allows Simpson to generate an organotypic structure with that same gene variant. This is a step towards finding personalized medicine specific for that patient.
Gene editing has also been used by other investigators in a 3D skin structure—made of keratinocytes similar to Simpson’s organoid skin—to reverse a genetic variant causing ichthyosis (Apaydin et al. 2026). Using lipid nanoparticles, a DNA editor was delivered to skin cells in which it corrected the sequence of the TGM1 gene. Skin diseases will be some of the most applicable for this technology because skin is easily accessed.
Repurposing drugs that are already on the market can accelerate rare disease trials, reducing costs, risks, and delays. “This can be a remarkable win for rare skin disease trials that are often harder to get off the ground than for more common conditions like eczema or psoriasis.”
The MEK inhibitor, trametinib, that had proven successful in Simpson’s preclinical model, was used to treat a patient with a severe case of Darier disease that was so debilitating that he was depressed and had suicidal thoughts (Soto-Garcia et al. 2025).
This patient had been treated with many different biologic therapies, which are currently used for conditions like psoriasis and atopic dermatitis, none of which worked for him.
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Dr. Aimee Payne’s Path to Creating CAAR-T Cell Therapies
Aimee S. Payne, MD, PhD received one of three highly competitive DF Stiefel Scholar Research Awards reserved for exceptional mid-career investigators.
“The dermatologist went to the hospital committee that controls charitable use of drugs and made an argument for using this medication [trametinib] because the patient was in such a severe state and nothing typical had worked for him,” Simpson said. It provided relief. “I spoke to the doctor six months after treatment and the patient was still doing well. ” Importantly, Simpson noted the importance of understanding long-term safety of oral MEK inhibitors, which could instead be delivered topically.
Organizations that advocate for rare diseases, including the NIH, realize that collectively rare diseases affect almost 10% of the population. Simpson argues that the bar for clinical studies might need to be lowered for ultra-rare diseases, to reduce the cost and barriers to entry for drug developers. In addition to testing a therapy for Darier disease, could it also be tested on a variety of disorders that also target the cohesion and maturation of keratinocytes, now categorized as epidermal differentiation disorders (EDDs)? This would be advantageous as it unites rare disease communities and could expand the impact of clinical advances from one disease to another.
In a symposium prior to the 2026 Society for Investigative Dermatology (SID) annual meeting, an entire day was devoted to EDDs (https://www.pachyonychia.org/2026-edd-symposium/), which include Darier and Hailey-Hailey disease.
Using organoid skin imaging to understand the way skin cells fall apart may lead to therapies, not just for rare inherited blistering disorders, but also for general wound healing and blistering diseases that are not genetic, like pemphigus. Pemphigus is caused by autoantibodies that recognize the substance that glues the cells together.
“Perhaps medications, like the ones that lead to MEK inhibition and make skin cells stick together more strongly, could be more widely applicable to common diseases that have similar pathology, even though one is immunologic and the other is genetic,” Simpson said. “An innovative aspect of studying rare diseases that is underappreciated is that creating genetic variation to model a disease can teach us about ‘normal’ biology. This could be useful for more common disorders.”
Simpson also studies Grover disease, a more prevalent blistering disorder with identical pathology to Darier disease. Despite having a different etiology, Grover disease also exhibits ERK hyperactivation suggestive that MEK inhibition might be a potential therapy (Simpson et al. 2024).
“Could MEK inhibitors even be used in eczema?” Simpson said. “It might tighten up the skin barrier, making it more impermeable to the allergens and other compounds that shouldn’t get in, and keeping water from evaporating as easily.”