Patient derived model of -associated encephalopathy identifies defects in neurodevelopment and highlights potential therapies.

encodes for the E1 enzyme of the UFMylation cascade, which plays an essential role in ER homeostasis. The clinical phenotypes of UBA5-associated encephalopathy include developmental delays, epilepsy and intellectual disability. To date, there is no humanized neuronal model to study the cellular and molecular consequences of pathogenic variants. We developed and characterized patient-derived cortical organoid cultures and identified defects in GABAergic interneuron development. We demonstrated aberrant neuronal firing and microcephaly phenotypes in patient-derived organoids. Mechanistically, we show that ER homeostasis is perturbed along with exacerbated unfolded protein response pathway in cells and organoids expressing pathogenic variants. We also assessed two gene expression modalities that augmented expression to rescue aberrant molecular and cellular phenotypes. Our study provides a novel humanized model that allows further investigations of variants in the brain and highlights novel systemic approaches to alleviate cellular aberrations for this rare, developmental disorder.