Inherited retinal disorders (IRDs) lead to vision loss and, in many cases, to complete blindness in those affected. Professor Uwe Wolfrum of the Institute of Molecular Physiology at Johannes Gutenberg University Mainz (JGU) is a leading researcher on a specific form of these disorders: the human Usher syndrome. In recognition of his scientific achievements in ophthalmology and vision research, Professor Wolfrum was recently honored by the renowned Institute of Ophthalmology at University College London (UCL).
Usher syndrome is the most common inherited disorder that causes both vision loss and deafness. Those affected can be deaf from birth and progressively lose their sight as the disease advances. While hearing loss can be managed with hearing aids or cochlear implants, there is currently no treatment for vision loss in patients with Usher syndrome. Wolfrum's team is investigating the molecular mechanisms in the eye that lead to vision loss in Usher syndrome. Based on findings from their basic research, they are paving the way for therapies aimed at preventing vision loss in patients with Usher syndrome.
Basic research unique in Germany – at the highest level
Usher syndrome is a clinically and genetically heterogeneous, recessively inherited disorder. To date, ten genes associated with Usher syndrome have been identified. The Mainz-based research group led by Professor Uwe Wolfrum is currently the only laboratory in Germany conducting cutting-edge research on Usher syndrome using state-of-the-art molecular and cell biological methods.
To elucidate the function of Usher syndrome proteins within the cell, researchers aim to identify proteins that interact with them and to analyze the resulting protein networks, known as interactomes. The research team investigates dysfunctions of the genes and proteins associated with Usher syndrome using models that replicate the specific cellular environment of the human eye. These include human retinal organoids—cellular models of the retina derived from patient-specific induced pluripotent stem cells (iPSCs)— along with pig models, as pigs' eyes are very similar in size, structure, and function to the human eye. The combination of these two Usher syndrome models and the possibility of conducting phenotypic studies that allow direct comparison between them are unique worldwide. These studies are expected to provide groundbreaking insights into the mechanisms underlying the human disease. Moreover, they could help reduce the need for animal experiments through the expanded use of human retinal organoids, and, in the long term, potentially replace them entirely.
From basic research to preclinical trials
In addition to investigating pathological changes in cell morphology using advanced microscopic techniques, the researchers use transcriptome and proteome analyses to identify dysregulated signaling pathways in both model systems. These approaches not only yield new insights into the pathomechanisms underlying Usher syndrome but also enable the identification of relevant disease biomarkers and novel therapeutic targets. Building on findings from basic research, the therapeutic team within Wolfrum's Mainz-based research group is currently conducting preclinical studies of gene-based therapeutic approaches for Usher syndrome in both model systems, with the aim of translating these approaches into clinical applications.
The research has been conducted in part within the framework of the DFG Priority Program SPP 2127 "Gene- and Cell-Based Therapies for the Treatment of Neuroretinal Degenerations" and Research Unit FOR 2149 "Elucidation of the Signaling Behavior of Adhesion-Dependent GPCRs", both funded by the German Research Foundation (DFG). It is primarily funded through grants from patient organizations, including the FAUN Foundation, Nuremberg; USHER2020, Atlanta; Pro Retina – Foundation for the Prevention of Blindness; and the Foundation Fighting Blindness.
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