Blood cancer therapy PKC412 shows promise in EBS cells: Study
Treatment eased blistering in 3D skin model of disorder
PKC412, a medication already used for treating certain blood cancers, has the potential to be repurposed for treating epidermolysis bullosa simplex (EBS), according to a preclinical study.
Using skin cells from people with various EBS-causing genetic mutations, scientists found that PKC412, also known as midostaurin, made the cells more resilient against stress and damage. In a newly developed three-dimensional (3D) EBS skin model, the treatment eased blistering.
“Repurposing of PKC412 as a therapy for EBS offers a targeted approach to enhance cellular resilience in this challenging condition,” researchers wrote.
The study, “Preclinical validation of PKC412 as a therapy candidate for epidermolysis bullosa simplex across multiple keratin pathogenic variants,” was published in the British Journal of Dermatology. It was funded by Debra Austria.
Existing medications could be repurposed for EBS
EBS is usually caused by mutations in the KRT5 or KRT14 genes. These mutations affect the organization and integrity of the keratin proteins that give structure to the outer layer of the skin, or epidermis.
Keratin proteins in EBS form abnormal clumps instead of assembling into their usually strong networks. Keratinocytes, the skin cells that produce keratins, become very fragile and prone to rupturing.
People with EBS thus have an epidermis that’s easily damaged and blistered, even with minor friction or pressure. In severe cases, the disease can also cause blistering in the mucous membranes that line body cavities.
Treatment for EBS largely relies on supportive care to manage symptoms and prevent complications. Identifying medications that are already used for other reasons and which could be repurposed for EBS may offer avenues for new therapeutic development, according to the authors.
PKC412 is approved in oral formulations (sold under the brand name Rydapt) for treating certain forms of blood cancer. It works to inhibit certain enzymes that play a role in cell growth and other cell-signaling pathways.
Previously, scientists found PKC412 prevented keratin clumping in cells derived from EBS patients and made the cells more resilient against stress.
PKC412 treatment restored cellular integrity, organization
In the recent study, the scientists further explored the potential of PKC412 as a repurposed EBS treatment. They investigated its effects in keratinocytes derived from EBS patients with a range of disease-causing mutations spanning milder and more severe forms of the disease.
The results showed the treatment enhanced the stability of keratinocyte networks, helping the cells better anchor together. In turn, keratinocytes were more resilient against damage when stretched.
To better replicate human EBS, the researchers developed a 3D epidermis model using the patients’ keratinocytes. They found the model reflected features of the disease, including easy blistering, but this was reduced with PKC412 treatment. The therapy also restored cellular integrity and organization.
These results indicate that PKC412 does not produce readily detectable adverse effects and provides important insights into the tolerability of PKC412 treatment on healthy skin.
In other experiments, PKC412 appeared to reduce a cellular modification to the desmoplakin protein called phosphorylation. Desmoplakin is involved in helping to form strong cellular networks in the epidermis, and its excessive phosphorylation has been associated with EBS.
Importantly, PKC412 appeared well tolerated in a healthy skin model, where it did not cause cell death or interfere with normal cell growth and maturation.
“These results indicate that PKC412 does not produce readily detectable adverse effects and provides important insights into the tolerability of PKC412 treatment on healthy skin,” the team noted.
PKC412 is used orally to treat cancer, but the researchers pointed out that systemic or local delivery to the skin could be beneficial for EBS.
While the results from these cell models are promising, the team emphasized that comprehensive studies in animal models will be important for establishing “clinical dosing regimens, application methods and long-term outcomes… in order to successfully translate our results to the clinical context.”
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