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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

TitleAdeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice
Authors
Issue Date2001
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
National Academy of Sciences Proceedings, 2001, v. 98 n. 5, p. 2676-2681 How to Cite?
Abstract
Fabry 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.
Persistent Identifierhttp://hdl.handle.net/10722/49404
ISSN
2013 Impact Factor: 9.809
PubMed Central ID
ISI Accession Number ID

 

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
DC FieldValueLanguage
dc.contributor.authorJung, SCen_HK
dc.contributor.authorHan, IPen_HK
dc.contributor.authorLimaye, Aen_HK
dc.contributor.authorXu, Ren_HK
dc.contributor.authorGelderman, MPen_HK
dc.contributor.authorZerfas, Pen_HK
dc.contributor.authorTirumalai, Ken_HK
dc.contributor.authorMurray, GJen_HK
dc.contributor.authorDuring, MJen_HK
dc.contributor.authorBrady, ROen_HK
dc.contributor.authorQasba, Pen_HK
dc.date.accessioned2008-06-12T06:41:39Z-
dc.date.available2008-06-12T06:41:39Z-
dc.date.issued2001en_HK
dc.identifier.citationNational Academy of Sciences Proceedings, 2001, v. 98 n. 5, p. 2676-2681en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/49404-
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.en_HK
dc.format.extent384 bytes-
dc.format.mimetypetext/html-
dc.languageengen_HK
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.rightsNational Academy of Sciences Proceedings. Copyright © National Academy of Sciences.en_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshDependovirus - geneticsen_HK
dc.subject.meshFabry Disease - enzymology - immunology - therapyen_HK
dc.subject.meshGene Transfer Techniquesen_HK
dc.subject.meshGenetic Vectorsen_HK
dc.subject.meshalpha-Galactosidase - genetics - metabolismen_HK
dc.titleAdeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry miceen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0027-8424&volume=98&issue=5&spage=2676&epage=2681&date=2001&atitle=Adeno-associated+viral+vector-mediated+gene+transfer+results+in+long-term+enzymatic+and+functional+correction+in+multiple+organs+of+Fabry+miceen_HK
dc.identifier.emailXu, R: rxua@hkucc.hku.hken_HK
dc.description.naturepublished_or_final_versionen_HK
dc.identifier.doi10.1073/pnas.051634498en_HK
dc.identifier.pmid11226298en_HK
dc.identifier.pmcidPMC30197en_HK
dc.identifier.scopuseid_2-s2.0-0035956882-
dc.identifier.hkuros69121-
dc.identifier.isiWOS:000167258900102-

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