title: Immunomodulatory gene therapy prevents antibody formation and lethal hypersensitivity reactions in murine pompe disease.
abstract: Infantile Pompe disease progresses to a lethal cardiomyopathy in absence of effective treatment. Enzyme-replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA) has been effective in most patients with Pompe disease, but efficacy was reduced by high-titer antibody responses. Immunomodulatory gene therapy with a low dose adeno-associated virus (AAV) vector (2 x 10(10) particles) containing a liver-specific regulatory cassette significantly lowered immunoglobin G (IgG), IgG1, and IgE antibodies to GAA in Pompe disease mice, when compared with mock-treated mice (P < 0.05). AAV-LSPhGAApA had the same effect on GAA-antibody production whether it was given prior to, following, or simultaneously with the initial GAA injection. Mice given AAV-LSPhGAApA had significantly less decrease in body temperature (P < 0.001) and lower anaphylactic scores (P < 0.01) following the GAA challenge. Mouse mast cell protease-1 (MMCP-1) followed the pattern associated with hypersensitivity reactions (P < 0.05). Regulatory T cells (Treg) were demonstrated to play a role in the tolerance induced by gene therapy as depletion of Treg led to an increase in GAA-specific IgG (P < 0.001). Treg depleted mice were challenged with GAA and had significantly stronger allergic reactions than mice given gene therapy without subsequent Treg depletion (temperature: P < 0.01; symptoms: P < 0.05). Ubiquitous GAA expression failed to prevent antibody formation. Thus, immunomodulatory gene therapy could provide adjunctive therapy in lysosomal storage disorders treated by enzyme replacement.
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Baodong
authors.initials: B
authors.lastname: Sun
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kulis
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Young
authors.forename: Amy C
authors.initials: AC
authors.lastname: Hobeika
authors.forename: Songtao
authors.initials: S
authors.lastname: Li
authors.forename: Andrew
authors.initials: A
authors.lastname: Bird
authors.forename: Haoyue
authors.initials: H
authors.lastname: Zhang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Li
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Clay
authors.forename: Wesley
authors.initials: W
authors.lastname: Burks
authors.forename: Priya S
authors.initials: PS
authors.lastname: Kishnani
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Koeberl
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics / Q000502:physiology*; D056947:Enzyme Replacement Therapy / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy / Q000379:methods*; D006009:Glycogen Storage Disease Type II / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D000520:alpha-Glucosidases / Q000235:genetics / Q000502:physiology
chemical_list: C509951:GAA protein, human; D000520:alpha-Glucosidases
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