title: 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.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Motas
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Haurigot
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Marcó
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Ribera
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Roca
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sánchez
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Sánchez
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Molas
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Bertolin
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
authors.forename: Luca
authors.initials: L
authors.lastname: Maggioni
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: León
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.|Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Ruberte
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000818:Animals; D000229:Dependovirus; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D007066:Iduronate Sulfatase / Q000235:genetics*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D016532:Mucopolysaccharidosis II / Q000628:therapy*
chemical_list: D007066:Iduronate Sulfatase