Although gene therapy has evolved rapidly during the last fifteen years into a promising therapeutic approach for genetic diseases, genetic replacement in the Central Nervous System (CNS) has remained an unconquered goal due to the inaccessibility of the brain and the spinal cord. Neurons and glial cells are highly sensitive to insults such as accumulation of toxic metabolites (i.e. in Lysosomal Storage Diseases), lack of an essential protein (i.e. in Pelizeus-Merzbacher Disease) or to autoimmune aggression (i.e. Multiple Sclerosis). The goal of this laboratory is to develop efficient gene replacement protocols to alleviate the devastating peripheral and central damage of two Lisosomal Storage Diseases: Metachromatic Leukodistrophy (MLD) and the Krabbe disease, or Globoid cells Leukodystrophy (GLD). By the use of lentiviral and retroviral vectors, we have been able to correct affected cells in vitro and to prevent to a great extent the development of the pathological phenotype in vivo, in the MLD mouse model. We are now exploring alternatives to enhance gene transfer into the brain. Recently, a new project has started, which evaluates the potential use of neural stem cells (NSCs) for in vivo cell therapy.