From gene transfer to gene therapy in lysosomal storage diseases affecting the 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 lysosomal storage diseases (LDS), which are an excellent model of both early-onset infantile neurological forms and late-onset adult psychiatric forms. Lysosomal storage diseases represent a group of about 50 monogenic metabolic disorders resulting from a deficiency in intralysosomal enzymes involved in macromolecule catabolism. The clinical severity, including neuropsychiatric symptoms, 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 the size of the corresponding cDNAs is generally compatible with their transfer by recombinant vectors. New vectors with improved immunogenicity, transduction efficacy, insert capacity, and specificity of targeting are under development. Here we discuss several gene therapy strategies for the correction of LSD-induced anomalies in the CNS. Interesting results have been obtained by animal model brain, which raises hopes that large-scale clinical trials may soon be started.