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dc.contributor.authorBaek, Rena C.
dc.contributor.authorBroekman, Marike L. D.
dc.contributor.authorLeroy, Stanley G.
dc.contributor.authorTierney, Laryssa A.
dc.contributor.authorSandberg, Michael Arthur
dc.contributor.authord'Azzo, Alessandra
dc.contributor.authorSeyfried, Thomas N.
dc.contributor.authorSena-Esteves, Miguel
dc.date.accessioned2011-04-16T00:40:32Z
dc.date.issued2010
dc.identifier.citationBaek, Rena C., Marike L. D. Broekman, Stanley G. Leroy, Laryssa A. Tierney, Michael A. Sandberg, Alessandra d'Azzo, Thomas N. Seyfried, and Miguel Sena-Esteves. 2010. AAV-Mediated Gene Delivery in Adult GM1-Gangliosidosis Mice Corrects Lysosomal Storage in CNS and Improves Survival. PLoS ONE 5(10): e13468.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:4851260
dc.description.abstractBackground: GM1-gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by a genetic deficiency of acid β-galactosidase (βgal), which results in the accumulation of GM1-ganglioside and its asialo-form (GA1) primarily in the CNS. Age of onset ranges from infancy to adulthood, and excessive ganglioside accumulation produces progressive neurodegeneration and psychomotor retardation in humans. Currently, there are no effective therapies for the treatment of GM1-gangliosidosis. Methodology/Principal Findings: In this study we examined the effect of thalamic infusion of AAV2/1-βgal vector in adult GM1 mice on enzyme distribution, activity, and GSL content in the CNS, motor behavior, and survival. Six to eight week-old GM1 mice received bilateral injections of AAV vector in the thalamus, or thalamus and deep cerebellar nuclei (DCN) with pre-determined endpoints at 1 and 4 months post-injection, and the humane endpoint, or 52 weeks of age. Enzyme activity was elevated throughout the CNS of AAV-treated GM1 mice and GSL storage nearly normalized in most structures analyzed, except in the spinal cord which showed ∼50% reduction compared to age-matched untreated GM1 mice spinal cord. Survival was significantly longer in AAV-treated GM1 mice (52 wks) than in untreated mice. However the motor performance of AAV-treated GM1 mice declined over time at a rate similar to that observed in untreated GM1 mice. Conclusions/Significance: Our studies show that the AAV-modified thalamus can be used as a ‘built-in’ central node network for widespread distribution of lysosomal enzymes in the mouse cerebrum. In addition, this study indicates that thalamic delivery of AAV vectors should be combined with additional targets to supply the cerebellum and spinal cord with therapeutic levels of enzyme necessary to achieve complete correction of the neurological phenotype in GM1 mice.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0013468en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956705/pdf/en_US
dash.licenseLAA
dc.subjectneurological disordersen_US
dc.subjectgenetics and genomicsen_US
dc.subjectgene therapyen_US
dc.subjectdevelopmental and pediatric neurologyen_US
dc.titleAAV-Mediated Gene Delivery in Adult GM1-Gangliosidosis Mice Corrects Lysosomal Storage in CNS and Improves Survivalen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorSandberg, Michael Arthur
dc.date.available2011-04-16T00:40:32Z
dash.affiliation.otherHMS^Ophthalmologyen_US
dc.identifier.doi10.1371/journal.pone.0013468*
dash.contributor.affiliatedSandberg, Michael


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