Human IPSC Technology to Investigate underlying mechanisms and potential therapeutic targets of Non-Syndromic XLID due to NEXMIF Gene Mutation

XLID-98 is a rare disorder linked to the NEXMIF gene, primarily affecting the nervous system. It manifests as developmental delay, intellectual disability, traits of autism spectrum disorders, speech difficulties, and epilepsy. As the condition is X-linked, symptoms differ between males and females. Studies in mouse models have shown that loss of NEXMIF gene function impairs neuronal development and migration, but the effect on human nerve cells has not been studied yet. With significant experience in basic research translated into clinical studies, our laboratory aims here to investigate the hypothesis that proteins such as NKCC1/KCC2 and Negr1 – already involved in several other neurodevelopmental disorders including autism spectrum disorders and epilepsy- may also play a role in XLID-98. We will use an in vitro model of human neurons engineered to replicate the NEXMIF-gene loss-of-function -typical of people with XLID-98- in two diverse experimental settings that replicate the male or the female condition. If confirmed, our hypothesis could lead to the repositioning of already approved drugs in the short-term, as has occurred for other brain diseases. Additionally, we will collect data using innovative "multi-omics" techniques to identify new therapeutic targets, creating a long-term backup/follow-up plan for the development of innovative drugs or targeted gene therapies in collaboration with pharmaceutical industries. The project aims to investigate new therapeutic options for XLID-98, with applications in both the short and long term.