Secret secretions: the story behind dysregulated extracellular matrixproteins in TCF4 expansion-mediated Fuchs Endothelial Corneal Dystrophy

• Applicant: Dr. Anne-Marie Shirley Kladny
• Subject Area: Ophthalmology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 527928847

Fuchs Endothelial Corneal Dystrophy (FECD) is the most common inherited corneal disease and a major cause of reduced vision and corneal transplantation. With demographic developments and rising life expectancy, the meaning of this age-related disease is increasing. In most cases, FECD is caused by a spelling mistake, a so-called ‘repeat expansion mutation’ of a triplet repeat element termed CTG18.1 of the transcription factor encoding gene TCF4. Still, it remains unclear how the CTG18.1 expansion causes the disease. So far, corneal transplantation is the only causal therapy. Non-surgical, donor tissue-independent pharmacological approaches are not fully developed. Additionally, biomarkers for validating the efficacy of therapies are needed. Extracellular matrix is a network of minerals and molecules that supports the adjacent cells structural and biochemical. It represents a fundamental contribution to the pathophysiology of FECD. Still, the mechanism is not fully understood. Studies investigating how the disease-causing genetic changes in FECD modify its clinical characteristics in correlation to the CTG18.1 expansion and studies investigating the histological differences between CTG18.1 expansion-positive (E-FECD) and CTG 18.1 expansion-negative FECD (NE-FECD) are insufficient. With this proposal, we thus aim to investigate the dysregulation of extracellular matrix (ECM) proteins in genetic data (= transcriptomic data from mRNA) and immunohistochemical observations for expansion positive corneas compared to expansion negative corneas and healthy controls. Therefore, corneal tissue that is removed as part of patients planned corneal transplantation will be used. This research will enable us to gain more in-depth knowledge about specific pathogenetic pathways in FECD, identify therapeutic target points and detect genetic and molecular biomarkers to develop and assess the efficacy of potential gene-directed therapeutics to improve vision and quality of life of patients with FECD. This research becomes even more important when acknowledging that CTG18.1-associated FECD is the most prevalent short tandem repeat expansion disease in humans. More than 50 human diseases belong to this category, especially other neurodegenerative, more severe, and life-shortening diseases like amyotrophic lateral sclerosis, and Huntington disease. Noticeable, the cornea, that is affected by FECD, can be removed, and examined comparatively easy and FECD is a relatively common disease. Improved knowledge of pathogenetic mechanism in E-FECD may guide treatment of other much rarer repeat-mediated diseases. Thus, the outcomes of this project will be beneficial to a diverse range of fields and of high relevance to scientists in academia and industry who are endeavouring to understand the molecular mechanisms of ophthalmic, triplet repeat-mediated and/or age-related diseases.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Privatdozentin Alice Davidson, Ph.D.