CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome)
Sandra Motas, Virginia Haurigot, Miguel Garcia, Sara Marcó, Albert Ribera, Carles Roca, Xavier Sánchez, Víctor Sánchez, Maria Molas, Joan Bertolin, Luca Maggioni, Xavier León, Jesús Ruberte, Fatima Bosch
Sandra Motas, Virginia Haurigot, Miguel Garcia, Sara Marcó, Albert Ribera, Carles Roca, Xavier Sánchez, Víctor Sánchez, Maria Molas, Joan Bertolin, Luca Maggioni, Xavier León, Jesús Ruberte, Fatima Bosch
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Research Article Neuroscience Therapeutics

CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome)

Abstract

Mucopolysaccharidosis type II (MPSII) is an X-linked lysosomal storage disease characterized by severe neurologic and somatic disease caused by deficiency of iduronate-2-sulfatase (IDS), an enzyme that catabolizes the glycosaminoglycans heparan and dermatan sulphate. Intravenous enzyme replacement therapy (ERT) currently constitutes the only approved therapeutic option for MPSII. However, the inability of recombinant IDS to efficiently cross the blood-brain barrier (BBB) limits ERT efficacy in treating neurological symptoms. Here, we report a gene therapy approach for MPSII through direct delivery of vectors to the CNS. Through a minimally invasive procedure, we administered adeno-associated virus vectors encoding IDS (AAV9-Ids) to the cerebrospinal fluid of MPSII mice with already established disease. Treated mice showed a significant increase in IDS activity throughout the encephalon, with full resolution of lysosomal storage lesions, reversal of lysosomal dysfunction, normalization of brain transcriptomic signature, and disappearance of neuroinflammation. Moreover, our vector also transduced the liver, providing a peripheral source of therapeutic protein that corrected storage pathology in visceral organs, with evidence of cross-correction of nontransduced organs by circulating enzyme. Importantly, AAV9-Ids-treated MPSII mice showed normalization of behavioral deficits and considerably prolonged survival. These results provide a strong proof of concept for the clinical translation of our approach for the treatment of Hunter syndrome patients with cognitive impairment.

Authors

Sandra Motas, Virginia Haurigot, Miguel Garcia, Sara Marcó, Albert Ribera, Carles Roca, Xavier Sánchez, Víctor Sánchez, Maria Molas, Joan Bertolin, Luca Maggioni, Xavier León, Jesús Ruberte, Fatima Bosch

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Figure 6

Normalization of CNS transcriptional signature following intra-CSF AAV9- Ids treatment.

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Normalization of CNS transcriptional signature following intra-CS...
Microarray expression analysis performed at 6 months of age in WT mice and mucopolysaccharidosis type II (MPSII) littermates 4 months after they received either AAV9-Null or AAV9-Ids vector injections. (A) Hierarchical clustering of all experimental groups based on the complete list of differentially expressed genes. Each row represents a gene and each column represents an animal. The expression of each gene is represented relative to the mean abundance of that gene across all samples in a color scale in which red and green indicate transcript levels above and below the mean, respectively. The magnitude of deviation from the mean is represented by the degree of color saturation. The dendrogram of samples shown above the matrix represents overall similarities in transcript levels. Visibly, the profile of gene expression in MPSII animals treated by intra-cerebrospinal fluid delivery of AAV9-Ids vectors resembles that of healthy age-matched WT littermates. (B) Functional categorization based on Gene Ontology annotation. Most of the categories depicted in the pie chart reflect processes associated with inflammation and innate immunity. (C) Similar analysis by hierarchical clustering as in A of the set of genes that the cell-type enrichment software assigned to be representative of microglia.