Metachromatic Leukodystrophy (MLD) is a rare demyelinating disease, due to arylsulfatase A (ARSA) deficiency, an enzyme involved in the catabolism of sulfatides, the main component of the myelin sheath. This deficiency leads to progressive demyelination of central nervous system and peripheral neuropathy. The most frequent form of the disease is the late infantile form of the disease which is characterized by a rapid progression of the disease, especially after the first onset of symptom. Ex vivo gene therapy develop by the group of Alessandra Biffi, and based on engraftment of lentiviral transduced hematopoietic stem cells has been shown to be effective for presymptomatic forms of MLD but not effective in early symptomatic patients, probably due to the rapid evolution and the time needed for the engrafment. On the other hand, enzyme replacement was shown as potentially effective but needed a chronic delivery. In the group, we previously proposed a gene therapy approach for MLD based on intracerebral delivery of an AAVrh.10 encoding ARSA. We had established proof of concept in mouse model of the disease and scale up study in non-human primates (NHP) leading us to propose a clinical trial which included 4 patients from 2013 to 2016. Despite ARSA expression in the brain and detection in cerebrospinal fluid (CSF) we failed to obtained any therapeutical benefits in these patients. Our point is that expressing ARSA in the CNS is fundamental to rapidly stop the disease progression, however, it could be essential also to bring back in patient healthy microglial cells. This project aim at establishing the proof of concept of rapid, sustained and important ARSA expression in the whole CNS (brain, spinal cord) and potentially also in the peripheral nerve. To achieve this aim, we propose to use a novel serotype of AAV: AAVPHP.eB that has been engineered to efficiently cross the blood brain barrier (BBB) after IV delivery. The project will be divided in two main parts, first a rapid study in the MLD mouse model both for pre and post symptomatic treatment, in order to evaluate efficiency of AAVPHP.eB-ARSA vector for biodistribution, ARSA expression, sulfatides correction, Purkinje cell prevention and behavioral testing. In a second phase, we want to test this vector in NHP thought several routes of delivery: intravenous (IV), intrathecal (IT) and intracerebroventricular (ICV), especially by potential coupling of these routes of administration to optimize CNS targeting. This with the final aim to propose a clinical trial for symptomatic MLD patients.

Project financed by ELA up to: 100 000 €