Gene-based approaches to inherited neurometabolic diseases.

In the last decade, the gene therapy field experienced a renaissance, thanks to crucial understandings and innovations in vector design, stem cell manipulation, conditioning protocols and cell/vector delivery. These efforts were successfully coupled to unprecedented clinical results of the trials employing the newly developed technology and to the novel establishment of academic-industrial partnerships. A renewed and strengthened interest is rising in the development of gene-based approaches for inherited neurometabolic disorders with severe neurological involvement. Inherited metabolic disorders are monogenetic diseases caused by enzymatic or structural deficiencies affecting the lysosomal or peroxisomal metabolic activity. The metabolic defect can primarily affect the central nervous system, leading to neuronal death, microglial activation, inflammatory demyelination and axonal degeneration. This review provides an overview of the gene therapy strategies currently under clinical investigation for neurometabolic Lysosomal and Peroxisomal Storage Diseases such as Adreno and Metachromatic Leukodystrophies, as well as novel emerging indications as Mucopolysaccharidoses, Gangliosidoses and Neuronal Ceroid Lipofuscinoses, with a comprehensive elucidation of the main features and mechanisms at the basis of a successful gene therapy approach for these devastating diseases.