Correction of pathological accumulation of glycosaminoglycans in central nervous system and peripheral tissues of MPSIIIA mice through systemic AAV9 gene transfer
Ruzo, Albert (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i de Teràpia Gènica (CBATEG))
Marcó, Sara (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Garcia, Miquel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Villacampa, Pilar (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Ribera Sánchez, Albert (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Ayuso, Eduard (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i de Teràpia Gènica (CBATEG))
Maggioni, Lucca (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Mingozzi, Federico (Children's Hospital of Philadelphia (Pennsilvània))
Haurigot Mendonça, Virginia (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Bosch i Tubert, Fàtima (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data:	2012
Resum:	Mucopolysaccharidosis type IIIA (MPSIIIA) is a rare lysosomal storage disorder caused by mutations in the sulfamidase gene. Accumulation of glycosaminoglycan (GAG) inside the lysosomes is associated with severe neurodegeneration as well as peripheral organ pathological changes leading to death of affected individuals during adolescence. There is no cure for MPSIIIA. Due to the limitation of the blood-brain barrier, enzyme replacement therapy and gene therapy strategies attempted thus far have not achieved whole-body correction of the disease. After the systemic administration of an adeno-associated virus 9 (AAV9) vector encoding for sulfamidase under the control of a ubiquitous promoter, we were able to obtain widespread expression of the therapeutic transgene in brain and in peripheral organs, and sulfamidase activity in serum of both male and female MPSIIIA mice. This was accompanied by the normalization of GAG storage levels in most peripheral organs. In brain, decrease in GAG tissue content following AAV9 gene transfer of sulfamidase was associated with the resolution of neuroinflammation. Finally, correction of disease phenotype resulted in a remarkable prolongation of survival of both male and female AAV-treated MPSIIIA mice. This proof-of-concept study will be relevant to the future development of therapies for MPSIIIA.
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Llengua:	Anglès
Document:	Article ; recerca ; Versió sotmesa a revisió
Matèria:	Lysosomal storage diseases ; Mucopolysaccharidosis Type IIIA ; Gene therapy ; Adeno-associated viral vectors ; Intravenous administration ; Central nervous system
Publicat a:	Human gene therapy, Vol. 23 Núm. 12 (Dec 2012) , p. 1237-1246, ISSN 1557-7422

DOI: 10.1089/hum.2012.029

28 p, 280.3 KB

10 p, 2.1 MB

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