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Lentiviral-mediated gene therapy for murine mucopolysaccharidosis type IIIA

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dc.contributor.authorMcIntyre, C.
dc.contributor.authorDerrick Roberts, A.
dc.contributor.authorRanieri, E.
dc.contributor.authorClements, P.
dc.contributor.authorByers, S.
dc.contributor.authorAnson, D.
dc.date.issued2008
dc.description.abstractMucopolysaccharidosis type IIIA (MPS IIIA) is a heritable glycosaminoglycan (GAG) storage disorder which is characterised by lysosomal accumulation of heparan sulphate, secondary to a deficiency of sulphamidase (heparan-N-sulphatase, N-sulphoglucosamine sulphohydrolase, EC No. 3.10.1.1.). There is currently no treatment for affected individuals who experience progressive CNS deterioration prior to an early death. As a first step towards developing gene therapy as a treatment for MPS IIIA, an MPS IIIA mouse model was used to examine the efficacy of intravenous lentiviral-mediated gene therapy. Five-week-old mice were injected with virus expressing murine sulphamidase and analysed 6 months after treatment. Transduction by the lentiviral vector was highest in the liver and spleen of treated animals, and sulphamidase activity in these tissues averaged 68% and 186% of normal, respectively. Storage was assessed using histochemical, chemical and mass spectrometric analyses. Storage in most somatic tissues was largely normalised, although chondrocytes were an obvious exception. Histologically, improvement of lysosomal storage within the brain was variable. However, beta-hexosaminidase activity, which is abnormally elevated in MPS IIIA, was significantly reduced in every treated tissue, including the brain. Total uronic acid was also significantly reduced in the brains of treated mice. The level of a disaccharide marker (hexosamine-N-sulphate[alpha-1,4]hexuronic acid; HNS-UA) of heparan sulphate storage was also decreased in the brains of treated mice, albeit non-significantly. These results suggest that lentiviral-mediated somatic gene transfer may affect not only the somatic, but possibly also the CNS pathology, found in MPS IIIA.
dc.description.statementofresponsibilityChantelle McIntyre, Ainslie Lauren Derrick Roberts, Enzo Ranieri, Peter Roy Clements, Sharon Byers and Donald S. Anson
dc.description.urihttp://www.elsevier.com/wps/find/journaldescription.cws_home/622920/description#description
dc.identifier.citationMolecular Genetics and Metabolism, 2008; 93(4):411-418
dc.identifier.doi10.1016/j.ymgme.2007.11.008
dc.identifier.issn1096-7192
dc.identifier.issn1096-7206
dc.identifier.orcidByers, S. [0000-0001-5576-3636]
dc.identifier.urihttp://hdl.handle.net/2440/51742
dc.language.isoen
dc.publisherAcademic Press Inc Elsevier Science
dc.source.urihttps://doi.org/10.1016/j.ymgme.2007.11.008
dc.subjectLiver
dc.subjectSpleen
dc.subjectLysosomes
dc.subjectAnimals
dc.subjectMice
dc.subjectLentivirus
dc.subjectMucopolysaccharidosis III
dc.subjectDisease Models, Animal
dc.subjectUronic Acids
dc.subjectHydrolases
dc.subjectDisaccharides
dc.subjectSpectrometry, Mass, Electrospray Ionization
dc.subjectBrain Chemistry
dc.subjectGenetic Vectors
dc.subjectMale
dc.subjectTandem Mass Spectrometry
dc.subjectbeta-N-Acetylhexosaminidases
dc.subjectGenetic Therapy
dc.titleLentiviral-mediated gene therapy for murine mucopolysaccharidosis type IIIA
dc.typeJournal article
pubs.publication-statusPublished

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