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dc.contributor.authorAhmed, Seemin Seher
dc.contributor.authorSchattgen, Stefan A.
dc.contributor.authorFrakes, Ashley E.
dc.contributor.authorSikoglu, Elif M.
dc.contributor.authorSu, Qin
dc.contributor.authorLi, Jia
dc.contributor.authorHampton, Thomas G.
dc.contributor.authorDenninger, Andrew R.
dc.contributor.authorKirschner, Daniel A.
dc.contributor.authorKaspar, Brian
dc.contributor.authorMatalon, Reuben
dc.contributor.authorGao, Guangping
dc.date2022-08-11T08:10:30.000
dc.date.accessioned2022-08-23T17:11:21Z
dc.date.available2022-08-23T17:11:21Z
dc.date.issued2016-06-01
dc.date.submitted2017-04-14
dc.identifier.citationMol Ther. 2016 Jun;24(6):1030-41. doi: 10.1038/mt.2016.68. Epub 2016 Apr 4. <a href="https://doi.org/10.1038/mt.2016.68">Link to article on publisher's site</a>
dc.identifier.issn1525-0016 (Linking)
dc.identifier.doi10.1038/mt.2016.68
dc.identifier.pmid27039844
dc.identifier.urihttp://hdl.handle.net/20.500.14038/46258
dc.description.abstractAspartoacylase (AspA) gene mutations cause the pediatric lethal neurodegenerative Canavan disease (CD). There is emerging promise of successful gene therapy for CD using recombinant adeno-associated viruses (rAAVs). Here, we report an intracerebroventricularly delivered AspA gene therapy regime using three serotypes of rAAVs at a 20-fold reduced dose than previously described in AspA(-/-) mice, a bona-fide mouse model of CD. Interestingly, central nervous system (CNS)-restricted therapy prolonged survival over systemic therapy in CD mice but failed to sustain motor functions seen in systemically treated mice. Importantly, we reveal through histological and functional examination of untreated CD mice that AspA deficiency in peripheral tissues causes morphological and functional abnormalities in this heretofore CNS-defined disorder. We demonstrate for the first time that AspA deficiency, possibly through excessive N-acetyl aspartic acid accumulation, elicits both a peripheral and CNS immune response in CD mice. Our data establish a role for peripheral tissues in CD pathology and serve to aid the development of more efficacious and sustained gene therapy for this disease.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=27039844&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttps://doi.org/10.1038/mt.2016.68
dc.subjectGenetics
dc.subjectNeurology
dc.subjectPsychiatry
dc.titlerAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System
dc.typeJournal Article
dc.source.journaltitleMolecular therapy : the journal of the American Society of Gene Therapy
dc.source.volume24
dc.source.issue6
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/psych_pp/795
dc.identifier.contextkey10023170
html.description.abstract<p>Aspartoacylase (AspA) gene mutations cause the pediatric lethal neurodegenerative Canavan disease (CD). There is emerging promise of successful gene therapy for CD using recombinant adeno-associated viruses (rAAVs). Here, we report an intracerebroventricularly delivered AspA gene therapy regime using three serotypes of rAAVs at a 20-fold reduced dose than previously described in AspA(-/-) mice, a bona-fide mouse model of CD. Interestingly, central nervous system (CNS)-restricted therapy prolonged survival over systemic therapy in CD mice but failed to sustain motor functions seen in systemically treated mice. Importantly, we reveal through histological and functional examination of untreated CD mice that AspA deficiency in peripheral tissues causes morphological and functional abnormalities in this heretofore CNS-defined disorder. We demonstrate for the first time that AspA deficiency, possibly through excessive N-acetyl aspartic acid accumulation, elicits both a peripheral and CNS immune response in CD mice. Our data establish a role for peripheral tissues in CD pathology and serve to aid the development of more efficacious and sustained gene therapy for this disease.</p>
dc.identifier.submissionpathpsych_pp/795
dc.contributor.departmentCenter for Comparative Neuroimaging, Department of Psychiatry
dc.contributor.departmentDepartment of Medicine
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.contributor.departmentHorae Gene Therapy Center
dc.source.pages1030-41


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