HSC-BASED EX VIVO GENE THERAPY OF METACHROMATIC AND GLOBOID LEUKODYSTROPHY

Metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD) are rare diseases consequent to the deficiency of enzymes, which are critical for synthesis, and maintenance of myelin in the nervous system. In both cases, the enzyme defect results in accumulation of toxic metabolites in affected tissues, particularly in the nervous system. Clinically, patients present signs and symptoms due to the progressive damage of the central and peripheral nervous system. The prognosis is severe leading to death, in the majority of the cases, few years after the diagnosis. No effective treatment is currently available. We are developing a gene therapy strategy for MLD and GLD, based on the transplantation of genetically corrected patients’ hematopoietic stem cells, the mother cells of blood elements. We already demonstrated the efficacy of this approach for delivery of the therapeutic enzyme to the affected nervous system. We have also shown its efficacy in preventing and correcting major disease manifestations in the mouse model of MLD. Encouraging results have also been obtained in GLD murine models. The project described here will be aimed at: i) establishing the conditions for safe and efficacious HSC-based ex vivo gene therapy for MLD in both murine models and patients’ cells, with the perspective of the starting clinical trial (see Project F3); ii) identifying the more efficacious therapeutic strategy for GLD, working on its different animal models; iii) better understanding the pathogenesis of MLD and GLD and the mechanisms of disease correction. Results obtained from this work will be crucial both for the ex vivo gene therapy trial in MLD patients, and for increasing our knowledge on the diseases and on the therapeutic potential of our approach.