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.
View: Text | PDF
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

×

Figure 3

Normalization of lysosomal homeostasis in the brain of MPSII mice following treatment with AAV9- Ids .

Options: View larger image (or click on image) Download as PowerPoint
Normalization of lysosomal homeostasis in the brain of MPSII mice...
(A) Representative images of the ultrastructural analysis of the cerebral cortex of WT and mucopolysaccharidosis type II (MPSII) mice performed 4 months after delivery of AAV9-Null or AAV9-Ids vectors to the cerebrospinal fluid. The perineuronal glial cells (noted as 1) associated with neurons (noted as 2) of the cerebral cortex of mice treated with AAV9-Ids did not show any of the large electrolucent vacuoles that could be clearly observed in the cytoplasm (indicated by red arrows) of cortical perineuronal glia in MPSII mice that received null vectors. n = 3. Scale bar: 2 μm. (B) Four months after gene transfer, the activity of lysosomal enzymes other than iduronate-2-sulfatase was analyzed in brain tissue extracts from all cohorts. WT activity was set to 100%. Treatment with AAV9-Ids restored the activities of N-sulphoglucosamine sulphohydrolase (SGSH), heparan-α-glucosaminide N-acetyltransferase (HGSNAT), galactosamine (N-acetyl)-6-sulfatase (GALNS), and β-hexosaminidase (β-HEXO) in the brain of treated MPSII mice. Data are shown as mean ± SEM of 4–5 animals/group. **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. MPSII+AAV9-Null (Dunnett’s test).