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Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy.
Haurigot Mendonça, Virginia (Centre de Biotecnologia Animal i de Teràpia Gènica)
Marcó, Sara
Ribera, Albert
Garcia, Miquel
Ruzo, Albert
Villacampa, Pilar
Ayuso López, Eduard (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
Añor Torres, Sònia (Universitat Autònoma de Barcelona. Departament de Medicina i Cirurgia Animal)
Andaluz Martínez, Anna (Universitat Autònoma de Barcelona. Departament de Medicina i Cirurgia Animals)
Pineda, Mercedes
García-Fructuoso, Gemma
Molas, Maria
Maggioni, Luca
Muñoz, Sergio
Motas, Sandra
Ruberte París, Jesús (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG))
Mingozzi, Federicco
Pumarola i Batlle, Martí (Universitat Autònoma de Barcelona. Departament de Medicina i Cirurgia)
Bosch i Tubert, Fàtima (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date: 2013
Abstract: For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA–affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement.
Rights: Aquest 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. Creative Commons
Language: Anglès.
Document: article ; recerca ; publishedVersion
Published in: The Journal of Clinical Investigation, Vol. 123 Núm. 8 (August 2013) , p. 3254-3271

DOI: 10.1172/JCI66778
PMID: 23863627

18 p, 12.2 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Unitat de Patologia Murina i Comparada
Articles > Research articles
Articles > Published articles

 Record created 2016-11-21, last modified 2019-05-15

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