Central nervous system delivery of helper-dependent canine adenovirus corrects neuropathology and behavior in mucopolysaccharidosis type VII mice

Ariza, L.; Gimenez-Llort, L.; Cubizolle, A.; Pages, G.; Garcia-Lareu, B.; Serratrice, N.; Cots, D.; Thwaite, R.; Chillon, M.; Kremer, E. J.; Bosch, A.

Hum Gene Ther

2014-03 / vol 25 / pages 199-211


Canine adenovirus type 2 vectors (CAV-2) are promising tools to treat global central nervous system (CNS) disorders because of their preferential transduction of neurons and efficient retrograde axonal transport. Here we tested the potential of a helper-dependent CAV-2 vector expressing beta-glucuronidase (HD-RIGIE) in a mouse model of mucopolysaccharidosis type VII (MPS VII), a lysosomal storage disease caused by deficiency in beta-glucuronidase activity. MPS VII leads to glycosaminoglycan accumulation into enlarged vesicles in peripheral tissues and the CNS, resulting in peripheral and neuronal dysfunction. After intracranial administration of HD-RIGIE, we show long-term expression of beta-glucuronidase that led to correction of neuropathology around the injection site and in distal areas. This phenotypic correction correlated with a decrease in secondary-elevated lysosomal enzyme activity and glycosaminoglycan levels, consistent with global biochemical correction. Moreover, HD-RIGIE-treated mice show significant cognitive improvement. Thus, injections of HD-CAV-2 vectors in the brain allow a global and sustained expression and may have implications for brain therapy in patients with lysosomal storage disease.

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1557-7422 (Electronic) 1043-0342 (Linking)


Animals; Mice; Disease Models, Animal; *Genetic Therapy; Dogs; Glycosaminoglycans/metabolism; Adenoviruses, Canine/*genetics; Behavior, Animal; Brain/immunology/metabolism/pathology; Enzyme Activation; Gene Expression; Genetic Vectors/administration & dosage/*genetics/immunology; Glucuronidase/*genetics/metabolism; Helper Viruses; Immunity, Innate; Injections; Lysosomes/enzymology; Microglia/immunology; Mucopolysaccharidosis VII/*genetics/*therapy; Transgenes

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