We expect to treat 20 patients, selected according to disease severity and clinical features. A myeloablative conditioning regimen based on iv Busulfan will be administered to the patients to enable engraftment of the transduced stem/progenitor cells in the bone marrow and enhance CNS microglia/macrophage repopulation by the transduced cell progeny. An efficient transduction protocol based on LVs has been optimized to guarantee abundant ARSA expression in the transduced patients' HSC and their progeny. In the treated patients, we will study the short-term and long-term safety of the administration of the autologous transduced HSC, their long-term engraftment, the expression of vector-derived ARSA, and the ability of the transduced cells to provide a clinical benefit to the patients. The treated patients will be followed for 3 years and thereafter monitored for the safety of gene therapy for additional 5 years. If successful, this study will provide key results on the safety and efficacy of gene therapy for MLD patients.