CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome)
Sandra Motas, … , Jesús Ruberte, Fatima Bosch
Sandra Motas, … , Jesús Ruberte, Fatima Bosch
Published June 16, 2016
Citation Information: JCI Insight. 2016;1(9):e86696. https://doi.org/10.1172/jci.insight.86696.
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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 1

IDS activity and GAG content in the CNS following intra-CSF delivery of AAV9 vectors.

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IDS activity and GAG content in the CNS following intra-CSF delivery of ...
(A) Analysis of iduronate-2-sulfatase (IDS) activity in different regions of the encephalon of healthy WT, untreated mucopolysaccharidosis type II (MPSII), and MPSII mice injected in the cerebrospinal fluid (CSF) either with 5 × 1010 vg/mouse of null vector (MPSII+AAV9-Null) or an equivalent dose of therapeutic vector (MPSII+AAV9-Ids). Four months after vector delivery (i.e., at 6 months of age) the encephalon of each animal was dissected and sectioned into 5 coronal sections (I–V), as indicated in the diagram above the plot. IDS activity of WT mice was set to 100%. Administration of AAV9-Ids restored IDS activity throughout the encephalon of treated MPSII mice. (B) Quantification of glycosaminoglycan (GAG) content in the same cohort of animals. AAV9-Ids delivery into the CSF resulted in full correction of GAG accumulation in all areas analyzed. Data are shown as mean ± SEM of 4–5 animals/group. ***P < 0.001, ****P < 0.0001 vs. MPSII+AAV9-Null (Dunnett’s test).