title: AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells.
abstract: In a clinical trial for adeno-associated virus serotype 1 (AAV-1)-mediated gene transfer to muscle for lipoprotein lipase (LPL) deficiency, 1 subject from the high-dose cohort experienced a transient increase in the muscle enzyme creatine phosphokinase (CPK) 4 weeks after gene transfer. Simultaneously, after an initial downward trend consistent with expression of LPL, plasma triglyceride levels returned to baseline. We characterized B- and T-cell responses to the vector and the transgene product in the subjects enrolled in this study. IFN-gamma enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining assays performed on peripheral blood mononuclear cells (PBMCs) from the subject who experienced the CPK elevation showed the activation of capsid-specific CD4(+) and CD8(+) T cells. Four of 8 subjects had detectable T-cell responses to capsid with dose-dependent kinetics of appearance. Subjects with detectable T-cell responses to capsid also had higher anti-AAV-1 IgG3 antibody titer. No subject developed B- or T-cell responses to the LPL transgene product. These findings suggest that T-cell responses directed to the AAV-1 capsid are dose-dependent. Whether they also limit the duration of expression of the transgene at higher doses is unclear, and will require additional analyses at later time points.
authors.affiliation: Division of Hematology and Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.forename: Janneke J
authors.initials: JJ
authors.lastname: Meulenberg
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hui
authors.forename: Etiena
authors.initials: E
authors.lastname: Basner-Tschakarjan
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Hasbrouck
authors.forename: Shyrie A
authors.initials: SA
authors.lastname: Edmonson
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Hutnick
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: John J
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Erik S
authors.initials: ES
authors.lastname: Stroes
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
mesh_terms: D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002213:Capsid / Q000276:immunology* / Q000378:metabolism; D003402:Creatine Kinase / Q000096:biosynthesis / Q000276:immunology; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008071:Lipoprotein Lipase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology / Q000276:immunology*; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics / Q000276:immunology*; D014280:Triglycerides / Q000097:blood
chemical_list: D000914:Antibodies, Viral; D007074:Immunoglobulin G; D014280:Triglycerides; D007371:Interferon-gamma; D003402:Creatine Kinase; D008071:Lipoprotein Lipase