Lysosomal storage disorders (LSD) are rare genetic diseases. Deficiency of specific lysosomal enzymes results in storage of undegraded macromolecules in lysosomes, functional impairment and cell death. Leukodystrophies (MLD, GLD) and GM2-gangliosidosis (Tay-Sachs and Sandhoff diseases) are “global” LSD affecting the nervous system and peripheral organs. Thus, an effective cure might require the implementation of innovative combined therapies. Previous studies established the therapeutic potential of gene/cell therapy in disease models with a mild phenotype (MLD), but its potential to cure severe and rapid progressive diseases (GLD and Sandhoff) remains to be determined. Our main goal is to develop novel combined gene- and neural stem cell (NSC)-based approaches to correct the metabolic defect and to restore the widespread tissue damage in murine models of LSD. In order to fully exploit the therapeutic potentials of NSCs we plan to study their biology in both physiological and pathological conditions.