Long-term therapeutic and mechanistic evalUation of metformiN in zebrafish and pAtient-derived cell models for NCLs diseases (LUNA)

This project aims to develop new therapies for a group of rare childhood brain diseases known as neuronal ceroid lipofuscinoses (NCLs), which cause progressive neurological decline. NCLs are among the most common pediatric neurodegenerative disorders and are characterized by lysosomal dysfunction, seizures, loss of motor and cognitive abilities, and premature death. Currently, there are no curative treatments, and only a few genetic subtypes have limited therapeutic options, leaving most patients without effective interventions. Our previous work showed that Metformin, a medication approved for treating diabetes mellitus, improves symptoms and cellular function in a zebrafish model of CLN8. We will now study the long-term effects of Metformin in adult zebrafish and analyze brain lipid changes, as well as test Metformin on patient cells from other NCLs forms. Cellular experiments will assess at what extent the drug will reduce harmful lipid droplets and restore autophagy. Our goal is to find effective treatments and reliable biomarkers to better manage and personalize therapy for NCLs patients.