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Prof Thomas Magin
Institution(s): Leipzig University, Institute of Biology, Working group of Cell & Developmental Biology
Research focus: Function analysis of keratins during epidermal differentiation, pathogenesis and regeneration
What are your own areas of research, and what insights do these give you on EB?
Our focus is on understanding pathomechanisms by which keratin K5 and K14 mutations cause EBS by collapsing the cytoskeleton into aggregates. We found that this collapse results from an interplay between keratin mutations and altered posttranslational modifications, leading to the hypothesis that aggregation can be reverted by interfering with posttranslational modifications, using specific drugs. Based on this, we have identified a drug that reduces keratin aggregation and improves keratinocyte adhesion. This drug is already in clinical use for the treatment of other diseases. It will not cure but significantly improve the quality of life of EBS patients. Our vision is to develop the drug such that it enables a topical or systemic application for EBS patients.
Where do you see the biggest contributions research can make to improving options for people with EB?
The development of Crispr/Cas-based gene scissors represents a milestone for the therapy of genetic diseases such as EB. Further research is necessary to make this treatment a safe option, in particular when it comes to the treatment of children. The success of Crispr/Cas-based gene therapy also depends on improvements in keratinocyte culture/transplantation for ex vivo approaches and on improving its safety for in situ therapy. Drug repurposing represents another topic to exploit the potential of existing drugs for the treatment of EB. In that respect, learning from related diseases such as Pachyonychia congenita could benefit EB patients. In parallel, we need to improve our understanding of EB pathomechanisms. In particular, inflammation, wound healing, tissue mechanics and aging-related phenomena are areas where we lack understanding their importance for EB.
What are the current most urgent research questions, both in basic knowledge and translational research?
The occurrence of cutaneous sqamous cell carcinoma represents represents the greatest burden in several forms of EB. While the role of TGFβ has emerged as one major driver, additional key biological drivers of SCC in
EB need to be identified. This will require –omics approaches and development of appropriate animal models. Further, the mechanisms linking EB gene mutations to inflammation and chronic wound healing defects need to be elucidated. Overall, the contribution of cell/ tissue mechanics, protein modifications and of protein quality control mechanisms to EB are very little understood but are likely to turn out druggable targets for molecular therapies. Translation of increased understanding will rely on appropriate animal models, an area that has been neglected for long. Therapies that rely on gene and siRNA transfer will benefit from improvements in cell culture, transfection technologies and vector developments. The power of chemical compounds that suppress inflammation, promote protein refolding and promote readthrough of premature translation codons has been recognized but will take more efforts to realize their potential.
DEBRA and EB-ResNet members are grateful for your dedication to helping people with EB; what do you find rewarding about being a member of MSAP?
Personally, I am grateful to the late Robin Eady to introduce me to EB and to DEBRA. This has given my research into the cell biology of the keratin cytoskeleton a completely different meaning. As a cell biologist, meeting colleagues from different disciplines has familiarized me with many facets and challenges of EB and is teaching me the complexity of EB, something I would have no chance to learn otherwise. Being member of the MSAP has definitely pushed my lab to consider how we can exploit our knowledge of keratin biology to develop a therapy approach for EBS. Since I am MSAP member, it has been rewarding for me to discuss directions of DEBRA-funded research.