Discussion

A major goal in the design of novel treatments for neurodegenerative lysosomal storage disorders (LSDs) is to achieve stable and widespread distribution of the therapeutic enzymes across the blood brain barrier in CNS tissues. We investigated here safety and therapeutic potential of intracerebral lentiviral gene therapy delivering functional lysosomal enzymes in non-human primates (NHPs). Given the unavailability of a NHP model of metachromatic leukodystrophy (MLD), we assessed intracerebral delivery of Arylsulfatase A (ARSA) in normal juvenile NHPs by using a lentiviral vector manufactured according to the process developed for ex vivo gene therapy clinical trial and targeting the expression of human ARSA transgene. Two unilateral injections in the white matter and in the thalamus were well tolerated. The procedure resulted in efficient gene transfer and robust transgene expression in neurons, astrocytes and oligodendrocytes, leading to persistent supraphysiological ARSA activity in the whole brain. Moderate local inflammation at the injection sites, mild immune response to lentiviral vector particles and no molecular evidence of insertional genotoxicity indicated a favorable safety profile of this approach. Importantly, delivery of LV.hGALC in a NHP model of globoid cell leukodystrophy (GLD) that recapitulates the human pathology resulted in similar broad CNS enzymatic reconstitution and positive safety profile. Our findings suggest that lentiviral vectors are attractive candidates for intracerebral gene therapy strategies addressing CNS pathology in LSD patients.