CLINICAL TRIAL OF GENE THERAPY IN METACHROMATIC LEUKODYSTROPHY

Metachromatic leukodystrophy (MLD) is a rare disease caused by the deficit of the enzyme arylsulfatase A (ARSA). It is characterized by signs and symptoms of involvement of central (CNS) and peripheral nervous (PNS) systems such as developmental delay or psychomotor regression, motor difficulties, disturbances in deglutition, blindness, deafness, and seizures. In the majority of cases, onset is within the first year of life and prognosis is very severe. No effective treatment is currently available. These observations prompted the identification and development of alternative therapeutic approaches, such as gene therapy. Our group during the previous grant period has developed an approach of gene therapy, called ex vivo, based on hematopoietic stem cells (HSC), the progenitors of all blood elements, and lentiviral vectors (LV), which are safe and effective vehicles to deliver the lacking gene into HSC. Through this approach it was possible to deliver the therapeutic enzyme to affected tissues, allowing prevention and correction of the major disease manifestations when applied to a murine model of MLD. Considering the characteristics of the disease and the encouraging results obtained from preclinical studies, we propose the ex vivo gene therapy approach for clinical translation. The results we obtained in the past three years from the monitoring of a large cohort of MLD patients provided relevant information for the identification of the best candidate patients for the clinical trial, and of the most reliable read outs to be used to monitor its efficacy. Therefore we plan to implement a clinical protocol for ex vivo gene therapy in HSC, the selection and enrollment of seven MLD patients, and the preliminary evaluation of safety and efficacy.