Identification of a novel disease mechanism and development of therapeutics for the recently identified neurodevelopmental disease “NEDAMSS”

NEDAMSS is a newly discovered neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures. The disease is caused by heterozygous mutations in the Interferon Regulatory Factor 2 Binding Protein-Like (IRF2BPL) gene. IRF2BPL is a ubiquitously expressed intron-less transcriptional regulator. The function of the protein is currently unknown, but the observed disease phenotype indicates a role in development and maintenance of the nervous system. To study this disease, we used patient skin-derived fibroblasts and reprogrammed them into induced neuronal progenitor cells (iNPCs). The iNPCs were then differentiated into astrocytes. Moreover, we also used a direct conversion method to generate neurons directly from the skin fibroblasts. Using these methods and performing molecular and functional analyses of the different cell types, we identified a novel disease mechanism not previously described. While IRF2BPL is localized in the nucleus in healthy individuals, we found that several patient cell lines displayed mis-localization in the form of aggregates in the cytoplasm. Moreover, the patient astrocytes also showed abnormal mitochondrial ATP-linked respiration levels and caused neuronal death in co-culture assays. Based on these observations, we tested treatment with CuATSM, a small molecule drug currently in clinical trials for ALS. We found that CuATSM successfully rescued neuronal survival and reduced ATP-linked respiration to normal levels in NEDAMSS astrocytes. We also established multiple AAV based gene therapy tools to modulate the expression of the protein and restore its normal function in vitro and potentially in vivo. In summary, we identified a novel disease mechanism involved in NEDAMSS disease and found promising therapeutic strategies that might be able to slow or halt the progression of the disease.