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dc.contributor.authorReddy, Adarsh S.
dc.contributor.authorKim, Joong H.
dc.contributor.authorHawkins-Salsbury, Jacqueline A.
dc.contributor.authorMacauley, Shannon L.
dc.contributor.authorTracy, Elisabeth T.
dc.contributor.authorVogler, Carole A.
dc.contributor.authorHan, Xialin
dc.contributor.authorSong, Sheng-Kwei
dc.contributor.authorWozniak, David F.
dc.contributor.authorFowler, Stephen C.
dc.contributor.authorKlein, Robyn S.
dc.contributor.authorSands, Mark S.
dc.date.accessioned2017-05-16T15:46:11Z
dc.date.available2017-05-16T15:46:11Z
dc.date.issued2011-07-06
dc.identifier.citationReddy, A. S., Kim, J. H., Hawkins-Salsbury, J. A., Macauley, S. L., Tracy, E. T., Vogler, C. A., … Sands, M. S. (2011). Bone Marrow Transplantation Augments the Effect of Brain- and Spinal Cord-Directed Adeno-Associated Virus 2/5 Gene Therapy by Altering Inflammation in the Murine Model of Globoid-Cell Leukodystrophy. The Journal of Neuroscience, 31(27), 9945–9957. http://doi.org/10.1523/JNEUROSCI.1802-11.2011en_US
dc.identifier.urihttp://hdl.handle.net/1808/24218
dc.description.abstractGloboid-cell leukodystrophy (GLD) is an inherited demyelinating disease caused by the deficiency of the lysosomal enzyme galactosylceramidase (GALC). A previous study in the murine model of GLD (twitcher) demonstrated a dramatic synergy between CNS-directed adeno-associated virus 2/5 (AAV2/5) gene therapy and myeloreductive bone marrow transplantation (BMT). However, the mechanism by which these two disparate therapeutic approaches synergize is not clear. In addition, the therapeutic efficacy may have been limited since the CNS-directed gene therapy was restricted to the forebrain and thalamus. In the current study, intrathecal and intracerebellar injections were added to the therapeutic regimen and the mechanism of synergy between BMT and gene therapy was determined. Although AAV2/5 alone provided supraphysiological levels of GALC activity and reduced psychosine levels in both the brain and spinal cord, it significantly increased CNS inflammation. Bone marrow transplantation alone provided essentially no GALC activity to the CNS and did not reduce psychosine levels. When AAV2/5 is combined with BMT, there are sustained improvements in motor function and the median life span is increased to 123 d (range, 92–282 d) compared with 41 d in the untreated twitcher mice. Interestingly, addition of BMT virtually eliminates both the disease and AAV2/5-associated inflammatory response. These data suggest that the efficacy of AAV2/5-mediated gene therapy is limited by the associated inflammatory response and BMT synergizes with AAV2/5 by modulating inflammation.en_US
dc.publisherSociety for Neuroscienceen_US
dc.rightsCopyright 2011, the authors. This work is being made available under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleBone Marrow Transplantation Augments the Effect of Brain- and Spinal Cord-Directed Adeno-Associated Virus 2/5 Gene Therapy by Altering Inflammation in the Murine Model of Globoid-Cell Leukodystrophyen_US
dc.typeArticleen_US
kusw.kuauthorFowler, Stephen C.
kusw.kudepartmentPharmacyen_US
dc.identifier.doi10.1523/JNEUROSCI.1802-11.2011en_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC3348856en_US
dc.rights.accessrightsopenAccess


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Copyright 2011, the authors.  This work is being made available under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.
Except where otherwise noted, this item's license is described as: Copyright 2011, the authors. This work is being made available under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.