From gene transfer to gene therapy in lysosomal storage diseases affectingthe central nervous system

Gene transfer into the central nervous system (CNS) is one of the foremost scientific challenges today. To give a brief survey of possible approaches to gene therapy in diseases affecting the CNS, we have selected the lysosom al storage diseases (LDS), which are an excellent model of both early-onset infantile neurological forms and late-onset adult psychiatric forms. Lysos omal storage diseases represent a group of about 50 monogenic metabolic dis orders resulting from a deficiency in intralysosomal enzymes involved in ma cromolecule catabolism. The clinical severity, including neuropsychiatric s ymptoms, and the absence of an efficient therapy for the majority of these disorders prompted the various trials of gene therapy now in progress. Most of the genes encoding the normal lysosomal enzymes have been cloned. and t he size of the corresponding cDNAs is generally compatible with their trans fer by recombinant vectors. New vectors with improved immunogenicity, trans duction efficacy, insert capacity, and specificity of targeting are under d evelopment. Here we discuss several gene therapy strategies for the correct ion of LSD-induced anomalies in the CNS. Interesting results have been obta ined by animal model brain, which raises hopes that large-scale clinical tr ials may soon be started.