| AAV2/5 vector expressing galactocerebrosidase ameliorates CNS disease in the murine model of globoid-cell leukodystrophy more efficiently than AAV2. | |
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MedLine Citation:
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PMID: 15996520 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Globoid-cell leukodystrophy (GLD) is an autosomal recessive lysosomal storage disorder caused by mutations in the galactosylceramidase (GALC) gene. Infantile GLD has a lethal course with severe cerebral demyelination that progresses to death by 2 years of age. In the current study twitcher mice, an authentic murine model of infantile GLD, were given intracranial injections of either recombinant adeno-associated virus serotype 2 encoding the murine Galc cDNA (AAV2-GALC) or the same genome pseudotyped with AAV5 capsid proteins (AAV2/5-GALC) on day 3 of age. The group injected intracranially with AAV2/5-GALC had approximately 25-fold greater than normal Galc levels in the brain, while AAV2-GALC-injected animals had 28% normal levels. The average life expectancy of twitcher mice ( approximately 38 days) was significantly (P < 0.0001) increased to 48 and 52 days for the AAV2-GALC- and AAV2/5-GALC-treated groups, respectively. The AAV2/5-GALC group performed significantly better in a battery of behavioral tests compared to untreated, AAV2-GFP-treated, or AAV2-treated twitcher animals. This longitudinal study demonstrated that AAV2/5-GALC-mediated gene therapy resulted in higher levels of Galc expression and slowed the neurologic deterioration more completely than AAV2-GALC in the murine model of globoid-cell leukodystrophy. However, the clinical improvements, as assessed by behavioral tests and life span, were only modest. |
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Authors:
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Darshong Lin; Corinne R Fantz; Beth Levy; Mohammad A Rafi; Carole Vogler; David A Wenger; Mark S Sands |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Molecular therapy : the journal of the American Society of Gene Therapy Volume: 12 ISSN: 1525-0016 ISO Abbreviation: Mol. Ther. Publication Date: 2005 Sep |
Date Detail:
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Created Date: 2005-08-15 Completed Date: 2005-11-23 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 100890581 Medline TA: Mol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 422-30 Citation Subset: IM |
Affiliation:
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Department of Internal Medicine, Washington University School of Medicine, Box 8007, 660 South Euclid Avenue, St. Louis, MO 63110, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Behavior, Animal Body Weight Brain / metabolism, pathology Central Nervous System Diseases / enzymology*, genetics DNA, Complementary / metabolism Dependovirus / genetics* Disease Models, Animal Galactosylceramidase / genetics* Gene Therapy / instrumentation*, methods Gene Transfer Techniques Genetic Vectors / genetics* Genotype Green Fluorescent Proteins / metabolism Homozygote Leukodystrophy, Globoid Cell / therapy* Mice Mutation Neurons / metabolism Phenotype Polymerase Chain Reaction Time Factors |
| Grant Support | |
ID/Acronym/Agency:
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DK 38795/DK/NIDDK NIH HHS; DK 57586/DK/NIDDK NIH HHS; MH 9453/MH/NIMH NIH HHS; MH 9471/MH/NIMH NIH HHS; NS 43205/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA, Complementary; 147336-22-9/Green Fluorescent Proteins; EC 3.2.1.46/Galactosylceramidase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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