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CpG-depleted adeno-associated virus vectors evade immune detection
Susan M. Faust, … , Joseph E. Rabinowitz, James M. Wilson
Susan M. Faust, … , Joseph E. Rabinowitz, James M. Wilson
Published June 17, 2013
Citation Information: J Clin Invest. 2013;123(7):2994-3001. https://doi.org/10.1172/JCI68205.
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Research Article Immunology Article has an altmetric score of 34

CpG-depleted adeno-associated virus vectors evade immune detection

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Abstract

Due to their efficient transduction potential, adeno-associated virus (AAV) vectors are leading candidates for gene therapy in skeletal muscle diseases. However, immune responses toward the vector or transgene product have been observed in preclinical and clinical studies. TLR9 has been implicated in promoting AAV-directed immune responses, but vectors have not been developed to circumvent this barrier. To assess the requirement of TLR9 in promoting immunity toward AAV-associated antigens following skeletal muscle gene transfer in mice, we compared immunological responses in WT and Tlr9-deficient mice that received an AAV vector with an immunogenic capsid, AAVrh32.33. In Tlr9-deficient mice, IFN-γ T cell responses toward capsid and transgene antigen were suppressed, resulting in minimal cellular infiltrate and stable transgene expression in target muscles. These findings suggest that AAV-directed immune responses may be circumvented by depleting the ligand for TLR9 (CpG sequences) from the vector genome. Indeed, we found that CpG-depleted AAVrh32.33 vectors could establish persistent transgene expression, evade immunity, and minimize infiltration of effector cells. Thus, CpG-depleted AAV vectors could improve outcome of clinical trials of gene therapy for skeletal muscle disease.

Authors

Susan M. Faust, Peter Bell, Benjamin J. Cutler, Scott N. Ashley, Yanqing Zhu, Joseph E. Rabinowitz, James M. Wilson

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Figure 1

LacZ expression in skeletal muscle of WT and Tlr9-KO mice following AAV gene transfer.

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LacZ expression in skeletal muscle of WT and Tlr9-KO mice following AAV ...
X-gal histochemical stain of muscle from WT and Tlr9-KO mice injected i.m. with 1 × 1011 GC of AAVrh32.33nLacZ (nuclear LacZ) (top 4 panels) and AAV8nlacZ (bottom 4 panels). Representative sections are shown. n = 4 mice per group. Original magnification, ×10.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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