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- W4309472919 abstract "Epidermolysis bullosa simplex (EBS) is a severe and potentially life-threatening disorder for which no adequate therapy exists. Most cases are caused by dominant mutations in keratins KRT5 or KRT14, characterized by cytoplasmic keratin aggregates, profound keratinocyte fragility and cytolysis. We hypothesized that pharmacological reduction of keratin aggregates, which compromise keratinocyte integrity, represents a viable strategy for the treatment of EBS. Here we show that the multi-kinase inhibitor PKC412, which is currently in clinical use for acute myeloid leukemia, reduced keratin aggregation by 40% in patient-derived K14. R125C EBS-associated keratinocytes. A combination of epithelial shear stress and real-time impedance spectroscopy assays revealed that PKC412 restored intercellular adhesion. Molecularly, global phosphoproteomic analysis together with immunoblots using phospho-epitope specific antibodies revealed that PKC412 treatment altered phospho-sites on keratins and desmoplakin. Thus, our data provide a proof of concept to repurpose existing drugs for the targeted treatment of EBS and showcase how one broad-range kinase inhibitor reduced keratin filament aggregation in patient-derived EBS keratinocytes and fragility of EBS cell monolayers. Our study paves the way for a clinical trial using PKC412 for systemic or local application in patients with EBS." @default.
- W4309472919 created "2022-11-28" @default.
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- W4309472919 date "2022-12-01" @default.
- W4309472919 modified "2023-09-25" @default.
- W4309472919 title "264 PKC412 prevents epithelial sheet damage in epidermolysis bullosa simplex via keratin and cell contact stabilization" @default.
- W4309472919 doi "https://doi.org/10.1016/j.jid.2022.09.276" @default.
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