AAV-1–mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells

• Published in: Blood Vol. 114; no. 10; pp. 2077 - 2086
• Main Authors: Mingozzi, Federico, Meulenberg, Janneke J., Hui, Daniel J., Basner-Tschakarjan, Etiena, Hasbrouck, Nicole C., Edmonson, Shyrie A., Hutnick, Natalie A., Betts, Michael R., Kastelein, John J., Stroes, Erik S., High, Katherine A.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 03.09.2009; Americain Society of Hematology; American Society of Hematology
• Series: Gene Therapy
• Subjects: Antibodies, Viral - blood; Antibodies, Viral - immunology; B-Lymphocytes - immunology; Biological and medical sciences; Capsid - immunology; Capsid - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Creatine Kinase - biosynthesis; Creatine Kinase - immunology; Dependovirus - genetics; Dependovirus - immunology; Dose-Response Relationship, Immunologic; Female; Fundamental and applied biological sciences. Psychology; Gene Therapy; Genetic Therapy; Humans; Hyperlipoproteinemia Type I - enzymology; Hyperlipoproteinemia Type I - genetics; Hyperlipoproteinemia Type I - immunology; Hyperlipoproteinemia Type I - therapy; Immunoenzyme Techniques; Immunoglobulin G - blood; Immunoglobulin G - immunology; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Lipoprotein Lipase - biosynthesis; Lipoprotein Lipase - genetics; Lipoprotein Lipase - immunology; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Male; Microbiology; Muscle, Skeletal - enzymology; Muscle, Skeletal - immunology; Techniques used in virology; Transduction, Genetic; Transgenes - genetics; Transgenes - immunology; Triglycerides - blood; Virology; Human; Adenoviridae; Acquired immunity; Cellular immunity; Activation; Striated muscle; Genetic transfer; Virus; Adenovirus 1; Human adenovirus; T-Lymphocyte; Mastadenovirus; Capsid; Gene therapy; Dose; Vector
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2008-07-167510

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-γ 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.