Glial promoter selectivity following AAV-delivery to the immature brain.

[canavan disease]

Recombinant adeno-associated virus (AAV ) vectors are versatile tools for gene transfer to the central nervous system (CNS ) and proof-of-concept studies in adult rodents have shown that the use of cell type -specific promoters is sufficient to target AAV-mediated transgene expression to glia . However , neurological disorders caused by glial pathology usually have an early onset . Therefore , modelling and treatment of these conditions require expanding the concept of targeted glial transgene expression by promoter selectivity for gene delivery to the immature CNS . Here , we have investigated the AAV-mediated green fluorescent protein (GFP ) expression driven by the myelin basic protein (MBP ) or glial fibrillary acidic protein (GFAP ) promoters in the developing mouse brain . Generally , the extent of transgene expression after infusion at immature stages was widespread and higher than in adults . The GFAP promoter-driven GFP expression was found to be highly specific for astrocytes following vector infusion to the brain of neonates and adults . In contrast , the selectivity of the MBP promoter for oligodendrocytes was poor following neonatal AAV delivery , but excellent after vector injection at postnatal day 10 . To extend these findings obtained in naïve mice to a disease model , we performed P 10 infusions of AAV-MBP -GFP in aspartoacylase (ASPA )-deficient mouse mutants presenting with early onset oligodendrocyte pathology . Spread of GFP expression and selectivity for oligodendrocytes in ASPA -mutants was comparable with our observations in normal animals . Our data suggest that direct AAV infusion to the developing postnatal brain , utilising cellular promoters , results in targeted and long -term transgene expression in glia . This approach will be relevant for disease modelling and gene therapy for the treatment of glial pathology .