Canine adenovirus type 2 vectors (CAV-2) are promising tools to treat global central nervous system (CNS) disorders due to their preferential transduction of neurons and efficient retrograde axonal transport. Here we tested the potential of a helper-dependent CAV-2 vector expressing ss-glucuronidase (HD-RIGIE) in a mouse model of mucopolysaccharidosis type VII (MPS VII), a lysosomal storage disease caused by deficiency in ss-glucuronidase activity. MPS VII leads to glycosaminoglycan accumulation into enlarged vesicles in peripheral tissues and the CNS, resulting in peripheral and neuronal dysfunction. Following intracranial administration of HD-RIGIE, we show long-term expression of ss-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 a brain therapy in patients with lysosomal storage disease.
Cns 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.; Bosch, A.
Hum Gene Ther
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