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Blood, 3 September 2009, Vol. 114, No. 10, pp. 2077-2086. Prepublished online as a Blood First Edition Paper on June 8, 2009; DOI 10.1182/blood-2008-07-167510.
GENE THERAPY AAV-1–mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells1 Division of Hematology and Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, PA; 2 Amsterdam Molecular Therapeutics, Amsterdam, The Netherlands; 3 Howard Hughes Medical Institute, Philadelphia, PA; 4 Department of Microbiology, University of Pennsylvania, Philadelphia; and 5 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
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-
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| Copyright © 2009 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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. 
