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

Lorena Ariza, Lydia Giménez-Llort, Aurélie Cubizolle, Gemma Pagès, Belén García-Lareu, Nicolas Serratrice, Dan Cots, Rosemary Thwaite, Miguel Chillón, Eric J. Kremer, Assumpció Bosch

Research output: Contribution to journalArticleResearchpeer-review

20 Citations (Scopus)

Abstract

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 β-glucuronidase (HD-RIGIE) in a mouse model of mucopolysaccharidosis type VII (MPS VII), a lysosomal storage disease caused by deficiency in β-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 β-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. © Copyright 2014, Mary Ann Liebert, Inc. 2014.
Original languageEnglish
Pages (from-to)199-211
JournalHuman Gene Therapy
Volume25
Issue number3
DOIs
Publication statusPublished - 1 Mar 2014

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