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 8

AAV9- Ids mediated correction of lysosomal pathology in somatic organs.

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AAV9- Ids mediated correction of lysosomal pathology...
(A) Representative images of the ultrastructural analysis of the hepatocytes and Kupffer cells of the liver, lung, and heart performed by transmission electron microscopy 4 months after intra-CSF delivery of vectors. MPSII+AAV9-Null, mucopolysaccharidosis type II (MSPII) mice receiving null vector; MSPII+AAV9-Ids, MPSII mice treated with therapeutic vector. Treated mice showed an evident reduction in the size and number of intracytoplasmic electrolucent vacuoles (red arrows) in all different tissues analyzed. CM, cardiac myocyte; V, blood vessel; M, macrophage-like cell. n = 3. Scale bar: 5 μm for hepatocytes and Kupffer cells; 2 μm for lung; 10 μm for heart. (B) Four months after gene transfer, the activity of a set of lysosomal enzymes other than IDS was analyzed. WT activity was set to 100% in all cases. Intra-CSF treatment with AAV9-Ids vectors restored the activities of α-L-iduronidase (IDUA), α-N-acetylglucosaminidase (NAGLU), heparan-α-glucosaminide N-acetyltransferase (HGSNAT), galactosamine (N-acetyl)-6-sulfatase (GALNS), β-glucuronidase (GUSB), and β-hexosaminidase (β-HEXO) in the liver. (C) Intra-CSF AAV9-Ids administration also resulted in correction of β-HEXO activity in serum. Data are shown as mean ± SEM of 4–5 animals/group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. MPSII+AAV9-Null (Dunnett’s test).