Researchers identify drug combinations that partially reverse rare genetic brain disorder
Scientists have used AI-guided drug screening to find that two existing compounds can partially restore normal cell behavior in patients with HNRNPU deficiency, a rare genetic cause of developmental delays. The findings, validated through protein analysis, could accelerate development of the first targeted therapy for this untreated patient population and demonstrate a replicable approach for rare disease drug discovery.
Originaltitel: Transcriptomic-guided compound prioritization and proteomics validation for <i>HNRNPU</i> deficiency identify signalling correction
Abstract Heterogeneous nuclear ribonucleoprotein U (HNRNPU) deficiency is a rare genetic cause of neurodevelopmental disorders (NDDs) lacking targeted therapies. Here, we developed a transcriptomic-guided compound prioritization pipeline using Connectivity Map (CMap) analysis on multi-model transcriptomic signatures from HNRNPU -deficient human cells and mouse models. Ten compounds were selected through manual curation and functionally screened in patient-derived HNRNPU -deficient neuroepithelial stem (NES) cells with earlier observed cellular phenotypes. Two of the compounds, AS601245 and Lenalidomide, significantly reduced the elevated neural progenitor population during differentiation, and their combination further decreased primary cilia incidence, indicating partial rescue of the patient-specific cellular phenotypes. To understand the mechanisms underlying the partial rescue, we employed proteome integral solubility alteration (PISA) and expression proteomics. PISA assay identified TMEM150C and GSK3A as proximal targets of combined treatment. Additionally, we observed reversal of multiple biological pathways including downregulation of Wnt signalling and upregulation of mitochondrial pathways and transmembrane proteins. Altogether, we established a computational-experimental pipeline for transcriptomic-guided drug repurposing for a monogenic NDD, and demonstrated that the network-level modulation partially rescues the delayed neural differentiation in HNRNPU -deficient neural cells.