Repurposing compound 1 to a therapy for Epidermolysis Bullosa Simplex (EBS) (Magin 5)Ongoing
|Project lead||Prof Thomas Magin|
|Organisation||University of Leipzig, Leipzig, GERMANY|
|Project budget||EUR 270,100.00|
|Start date / Duration||01. Jul 2022 / 36 months|
|Funder(s) / Co-Funder(s)||DEBRA Austria, MSAP/EBEP Recommended|
|Research area||Molecular therapy, Cellular therapy|
Short lay summary
Mutations in keratin genes KRT5 or KRT14 cause EB simplex by promoting the collapse of the skin cells cell skeleton into protein clumps which fails to protect skin cells against forces from stretching, rubbing and pushing. Like other forms of EB, EBS can in principle be cured by gene therapy. However, the notion that many EBS patients experience an improvement of their condition during adult life, call for alternative, less invasive treatment regimes that improve sufferers’ skin condition and their overall quality of life. This project follows the strategy to screen for existing drugs that reduce keratin aggregation and to improve skin cell cohesion. Our vision is to apply such drugs locally to affected areas as a cream. The team has now identified such a drug (a kinase inhibitor) that is already in clinical use for other diseases which should reduce the effort to move this drug forward to a clinical study. This project aims at optimizing the conditions for drug application in several skin cell models and to develop a cream formulation of the drug.
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, leading to the formation of cytoplasmic keratin aggregates, profound keratinocyte fragility and cytolysis. The team hypothesized that pharmacological reduction of keratin aggregates, which compromise keratinocyte integrity, represents a viable strategy for the treatment of EBS. Prof Magin’s team found that the multi-kinase inhibitor PKC412, which is currently in clinical use for acute myeloid leukemia and advanced systemic mastocytosis, reduced keratin aggregation by 40% in patient-derived K14.R125C EBS-associated keratinocytes. Using a combination of epithelial shear stress assay and real-time impedance spectroscopy, it was shown 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, the 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. During the funding period, the project team will focus on the following topics: 1. PKC412 application in primary and immortalized K14.R125C keratinocytes and in humanized mice; 2. Suitability of PKC412 for additional K5 and K14 mutations; 3. Characterization of PKC412 under conditions of mechanical stress and in human skin explants. This study will pave the way for a clinical trial using PKC412 for systemic or local application in patients with EBS.
Together with collaborators, Prof. M.B. Omary (Rutgers University) and C. Has (Dermatology, Freiburg University), the team lead by Prof Magin will develop PKC412 into a cream for local application and prepare for a clinical study if our results support this.