CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome)
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 t...
| Autores: | , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:306282 |
| Acceso en línea: | https://ddd.uab.cat/record/306282 https://dx.doi.org/urn:doi:10.1172/jci.insight.86696 |
| Access Level: | acceso abierto |
| Palabra clave: | Animals Dependovirus Disease Models Genetic Therapy Genetic Vectors Iduronate Sulfatase 129 Strain Inbred C57BL Mucopolysaccharidosis II/therapy |
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CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome)Motas, Sandra|||0000-0003-2748-5952Haurigot Mendonça, Virginia|||0000-0002-9772-2565Garcia, Miquel|||0000-0002-1602-4993Marcó, Sara|||0000-0003-3502-5198Ribera Sánchez, Albert|||0000-0002-7120-4276Roca Lecha, Carles|||0000-0002-3744-3089Sanchez Moreno, Xavier|||0000-0003-0897-0661Sánchez, VíctorMolas, MariaBertolín Gálvez, Joan|||0000-0002-5196-0955Maggioni, LucaLeón, Xavier|||0000-0002-8393-2721Ruberte Paris, Jesús|||0000-0003-1540-1432Bosch i Tubert, Fàtima|||0000-0002-7705-5515AnimalsDependovirusDisease ModelsGenetic TherapyGenetic VectorsIduronate Sulfatase129 StrainInbred C57BLMucopolysaccharidosis II/therapyMucopolysaccharidosis 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. 22016-01-0120162016-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/306282https://dx.doi.org/urn:doi:10.1172/jci.insight.86696reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Economía y Competitividad https://doi.org/10.13039/501100003329 IPT-2012-0772-300000Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2014-54866-RGeneralitat de Catalunya https://doi.org/10.13039/501100002809 2014SGR-1669open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3062822026-06-06T12:50:31Z |
| dc.title.none.fl_str_mv |
CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome) |
| title |
CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome) |
| spellingShingle |
CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome) Motas, Sandra|||0000-0003-2748-5952 Animals Dependovirus Disease Models Genetic Therapy Genetic Vectors Iduronate Sulfatase 129 Strain Inbred C57BL Mucopolysaccharidosis II/therapy |
| title_short |
CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome) |
| title_full |
CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome) |
| title_fullStr |
CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome) |
| title_full_unstemmed |
CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome) |
| title_sort |
CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome) |
| dc.creator.none.fl_str_mv |
Motas, Sandra|||0000-0003-2748-5952 Haurigot Mendonça, Virginia|||0000-0002-9772-2565 Garcia, Miquel|||0000-0002-1602-4993 Marcó, Sara|||0000-0003-3502-5198 Ribera Sánchez, Albert|||0000-0002-7120-4276 Roca Lecha, Carles|||0000-0002-3744-3089 Sanchez Moreno, Xavier|||0000-0003-0897-0661 Sánchez, Víctor Molas, Maria Bertolín Gálvez, Joan|||0000-0002-5196-0955 Maggioni, Luca León, Xavier|||0000-0002-8393-2721 Ruberte Paris, Jesús|||0000-0003-1540-1432 Bosch i Tubert, Fàtima|||0000-0002-7705-5515 |
| author |
Motas, Sandra|||0000-0003-2748-5952 |
| author_facet |
Motas, Sandra|||0000-0003-2748-5952 Haurigot Mendonça, Virginia|||0000-0002-9772-2565 Garcia, Miquel|||0000-0002-1602-4993 Marcó, Sara|||0000-0003-3502-5198 Ribera Sánchez, Albert|||0000-0002-7120-4276 Roca Lecha, Carles|||0000-0002-3744-3089 Sanchez Moreno, Xavier|||0000-0003-0897-0661 Sánchez, Víctor Molas, Maria Bertolín Gálvez, Joan|||0000-0002-5196-0955 Maggioni, Luca León, Xavier|||0000-0002-8393-2721 Ruberte Paris, Jesús|||0000-0003-1540-1432 Bosch i Tubert, Fàtima|||0000-0002-7705-5515 |
| author_role |
author |
| author2 |
Haurigot Mendonça, Virginia|||0000-0002-9772-2565 Garcia, Miquel|||0000-0002-1602-4993 Marcó, Sara|||0000-0003-3502-5198 Ribera Sánchez, Albert|||0000-0002-7120-4276 Roca Lecha, Carles|||0000-0002-3744-3089 Sanchez Moreno, Xavier|||0000-0003-0897-0661 Sánchez, Víctor Molas, Maria Bertolín Gálvez, Joan|||0000-0002-5196-0955 Maggioni, Luca León, Xavier|||0000-0002-8393-2721 Ruberte Paris, Jesús|||0000-0003-1540-1432 Bosch i Tubert, Fàtima|||0000-0002-7705-5515 |
| author2_role |
author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Animals Dependovirus Disease Models Genetic Therapy Genetic Vectors Iduronate Sulfatase 129 Strain Inbred C57BL Mucopolysaccharidosis II/therapy |
| topic |
Animals Dependovirus Disease Models Genetic Therapy Genetic Vectors Iduronate Sulfatase 129 Strain Inbred C57BL Mucopolysaccharidosis II/therapy |
| description |
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. |
| publishDate |
2016 |
| dc.date.none.fl_str_mv |
2 2016-01-01 2016 2016-01-01 |
| dc.type.none.fl_str_mv |
Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://ddd.uab.cat/record/306282 https://dx.doi.org/urn:doi:10.1172/jci.insight.86696 |
| url |
https://ddd.uab.cat/record/306282 https://dx.doi.org/urn:doi:10.1172/jci.insight.86696 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 IPT-2012-0772-300000 Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2014-54866-R Generalitat de Catalunya https://doi.org/10.13039/501100002809 2014SGR-1669 |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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reponame:Dipòsit Digital de Documents de la UAB instname:Universitat Autònoma de Barcelona |
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Universitat Autònoma de Barcelona |
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