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Article: Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice
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TitleAdeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice
 
AuthorsJung, SC5
Han, IP5
Limaye, A5
Xu, R4
Gelderman, MP5
Zerfas, P1
Tirumalai, K2
Murray, GJ5
During, MJ4 3
Brady, RO5
Qasba, P5 1
 
Issue Date2001
 
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
CitationNational Academy of Sciences Proceedings, 2001, v. 98 n. 5, p. 2676-2681 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.051634498
 
AbstractFabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). This enzyme deficiency leads to impaired catabolism of alpha-galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop painful neuropathy and vascular occlusions that progressively lead to cardiovascular, cerebrovascular, and renal dysfunction and early death. Although enzyme replacement therapy and bone marrow transplantation have shown promise in the murine analog of Fabry disease, gene therapy holds a strong potential for treating this disease in humans. Delivery of the normal alpha-gal A gene (cDNA) into a depot organ such as liver may be sufficient to elicit corrective circulating levels of the deficient enzyme. To investigate this possibility, a recombinant adeno-associated viral vector encoding human alpha-gal A (rAAV-AGA) was constructed and injected into the hepatic portal vein of Fabry mice. Two weeks postinjection, alpha-gal A activity in the livers of rAAV-AGA-injected Fabry mice was 20-35% of that of the normal mice. The transduced animals continued to show higher alpha-gal A levels in liver and other tissues compared with the untouched Fabry controls as long as 6 months after treatment. In parallel to the elevated enzyme levels, we see significant reductions in Gb3 levels to near normal at 2 and 5 weeks posttreatment. The lower Gb3 levels continued in liver, spleen, and heart, up to 25 weeks with no significant immune response to the virus or alpha-gal A. Also, no signs of liver toxicity occurred after the rAAV-AGA administration. These findings suggest that an AAV-mediated gene transfer may be useful for the treatment of Fabry disease and possibly other metabolic disorders.
 
ISSN0027-8424
2012 Impact Factor: 9.737
2012 SCImago Journal Rankings: 5.473
 
DOIhttp://dx.doi.org/10.1073/pnas.051634498
 
PubMed Central IDPMC30197
 
ISI Accession Number IDWOS:000167258900102
 
DC FieldValue
dc.contributor.authorJung, SC
 
dc.contributor.authorHan, IP
 
dc.contributor.authorLimaye, A
 
dc.contributor.authorXu, R
 
dc.contributor.authorGelderman, MP
 
dc.contributor.authorZerfas, P
 
dc.contributor.authorTirumalai, K
 
dc.contributor.authorMurray, GJ
 
dc.contributor.authorDuring, MJ
 
dc.contributor.authorBrady, RO
 
dc.contributor.authorQasba, P
 
dc.date.accessioned2008-06-12T06:41:39Z
 
dc.date.available2008-06-12T06:41:39Z
 
dc.date.issued2001
 
dc.description.abstractFabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). This enzyme deficiency leads to impaired catabolism of alpha-galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop painful neuropathy and vascular occlusions that progressively lead to cardiovascular, cerebrovascular, and renal dysfunction and early death. Although enzyme replacement therapy and bone marrow transplantation have shown promise in the murine analog of Fabry disease, gene therapy holds a strong potential for treating this disease in humans. Delivery of the normal alpha-gal A gene (cDNA) into a depot organ such as liver may be sufficient to elicit corrective circulating levels of the deficient enzyme. To investigate this possibility, a recombinant adeno-associated viral vector encoding human alpha-gal A (rAAV-AGA) was constructed and injected into the hepatic portal vein of Fabry mice. Two weeks postinjection, alpha-gal A activity in the livers of rAAV-AGA-injected Fabry mice was 20-35% of that of the normal mice. The transduced animals continued to show higher alpha-gal A levels in liver and other tissues compared with the untouched Fabry controls as long as 6 months after treatment. In parallel to the elevated enzyme levels, we see significant reductions in Gb3 levels to near normal at 2 and 5 weeks posttreatment. The lower Gb3 levels continued in liver, spleen, and heart, up to 25 weeks with no significant immune response to the virus or alpha-gal A. Also, no signs of liver toxicity occurred after the rAAV-AGA administration. These findings suggest that an AAV-mediated gene transfer may be useful for the treatment of Fabry disease and possibly other metabolic disorders.
 
dc.description.naturepublished_or_final_version
 
dc.format.extent384 bytes
 
dc.format.mimetypetext/html
 
dc.identifier.citationNational Academy of Sciences Proceedings, 2001, v. 98 n. 5, p. 2676-2681 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.051634498
 
dc.identifier.doihttp://dx.doi.org/10.1073/pnas.051634498
 
dc.identifier.hkuros69121
 
dc.identifier.isiWOS:000167258900102
 
dc.identifier.issn0027-8424
2012 Impact Factor: 9.737
2012 SCImago Journal Rankings: 5.473
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC30197
 
dc.identifier.pmid11226298
 
dc.identifier.scopuseid_2-s2.0-0035956882
 
dc.identifier.urihttp://hdl.handle.net/10722/49404
 
dc.languageeng
 
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
dc.rightsNational Academy of Sciences Proceedings. Copyright © National Academy of Sciences.
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subject.meshDependovirus - genetics
 
dc.subject.meshFabry Disease - enzymology - immunology - therapy
 
dc.subject.meshGene Transfer Techniques
 
dc.subject.meshGenetic Vectors
 
dc.subject.meshalpha-Galactosidase - genetics - metabolism
 
dc.titleAdeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice
 
dc.typeArticle
 
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<contributor.author>Zerfas, P</contributor.author>
<contributor.author>Tirumalai, K</contributor.author>
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<contributor.author>During, MJ</contributor.author>
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<subject.mesh>Dependovirus - genetics</subject.mesh>
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Author Affiliations
  1. National Institute of Neurological Disorders and Stroke
  2. National Institute of Allergy and Infectious Diseases
  3. Thomas Jefferson University
  4. School of Medicine, University of Auckland
  5. National Institutes of Health, Bethesda