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Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease.

dc.contributor.author Clay, TM
dc.contributor.author Kemper, Alex Randall
dc.contributor.author Koeberl, Dwight D
dc.contributor.author Luo, X
dc.contributor.author Osada, Takuya
dc.contributor.author Rodriguiz, Ramona M
dc.contributor.author Sun, Baodong
dc.contributor.author Yang, XY
dc.contributor.author Zhang, P
dc.coverage.spatial United States
dc.date.accessioned 2017-07-24T14:42:12Z
dc.date.available 2017-07-24T14:42:12Z
dc.date.issued 2012-05
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/22260439
dc.identifier.uri http://hdl.handle.net/10161/15089
dc.description.abstract Pompe disease can be treated effectively, if immune tolerance to enzyme replacement therapy (ERT) with acid α-glucosidase (GAA) is present. An adeno-associated viral (AAV) vector carrying a liver-specific regulatory cassette to drive GAA expression (AAV-LSPhGAA) established immune tolerance in GAA knockout (KO) mice, whereas ubiquitous expression with AAV-CBhGAA provoked immune responses. Therefore, we investigated the hypothesis that immune tolerance induced by hepatic-restricted expression was dominant. AAV-LSPhGAA and AAV-CBhGAA were administered singly or in combination to groups of adult GAA-KO mice, and AAV-LSPhGAA induced immune tolerance even in combination with AAV-CBhGAA. The dual vector approach to GAA expression improved biochemical correction of GAA deficiency and glycogen accumulations at 18 weeks, and improved motor function testing including wire-hang and grip-strength testing. The greatest efficacy was demonstrated by dual vector administration, when both vectors were pseudotyped as AAV8. T cells from mice injected with AAV-LSPhGAA failed to proliferate at all after an immune challenge with GAA and adjuvant, whereas mock-treated GAA-KO mice mounted vigorous T cell proliferation. Unlike AAV-LSPhGAA, AAV-CBhGAA induced selective cytokine and chemokine expression in liver and spleen after the immune challenge. AAV-CBhGAA transduced dendritic cells and expressed high-level GAA, whereas AAV-LSPhGAA failed to express GAA in dendritic cells. The level of transduction in liver was much higher after dual AAV8 vector administration at 18 weeks, in comparison with either vector alone. Dual vector administration failed to provoke antibody formation in response to GAA expression with AAV-CBhGAA; however, hepatic-restricted expression from dual vector expression did not prevent antibody formation after a strong immune challenge with GAA and adjuvant. The relevance of immune tolerance to gene therapy in Pompe disease indicates that hepatic expression might best be combined with nonhepatic expression, achieving the benefits of ubiquitous expression in addition to evading deleterious immune responses.
dc.language eng
dc.relation.ispartof Hum Gene Ther
dc.relation.isversionof 10.1089/hum.2011.063
dc.subject Animals
dc.subject Cell Proliferation
dc.subject Cells, Cultured
dc.subject Dendritic Cells
dc.subject Dependovirus
dc.subject Enzyme Replacement Therapy
dc.subject Genetic Therapy
dc.subject Genetic Vectors
dc.subject Glycogen Storage Disease Type II
dc.subject Humans
dc.subject Immune Tolerance
dc.subject Immunoglobulin G
dc.subject Injections, Intravenous
dc.subject Liver
dc.subject Mice
dc.subject Mice, Inbred Strains
dc.subject Mice, Knockout
dc.subject Organ Specificity
dc.subject T-Lymphocytes
dc.subject Transgenes
dc.subject alpha-Glucosidases
dc.title Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease.
dc.type Journal article
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/22260439
pubs.begin-page 460
pubs.end-page 472
pubs.issue 5
pubs.organisational-group Basic Science Departments
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Community and Family Medicine
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Duke Clinical Research Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group Pediatrics
pubs.organisational-group Pediatrics, Medical Genetics
pubs.organisational-group Pediatrics, Primary Care Pediatrics
pubs.organisational-group School of Medicine
pubs.organisational-group Surgery
pubs.organisational-group Surgery, Surgical Sciences
pubs.publication-status Published
pubs.volume 23
dc.identifier.eissn 1557-7422


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