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Weakly immunogenic CRISPR therapies

Nature Biomedical Engineering volume 3, pages 761–762 (2019)Cite this article

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Orthologues of CRISPR-associated proteins and of viral vectors evade immune recognition in mice, enabling repeated gene therapy.

The death of 18-year-old Jesse Gelsinger during a gene therapy trial in 1999, presumably owing to a fulminant immune response to the adenoviral vector used in the study, triggered increased federal regulation for gene therapies1. Since then, multiple studies have shown that effective gene delivery may be limited by both pre-existing and induced immune responses to exogenous proteins derived from the transgene or from the viral vector2,3. Clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) is now enabling a new generation of precision gene therapies, but the potential for immunotoxicity — in particular to the Cas9 transgene — remains a concern. In an early murine model, hepatic delivery of Streptococcus pyogenes Cas9 (SpCas9) with a common type of adenovirus (the E1/E3-deleted Ad5 vector) targeting endogenous Pten resulted in adenovirus-specific immune responses and in T-cell and B-cell immunity to SpCas9 (ref. 4). These events triggered hepatic inflammation and liver damage within 14 days of injection. A less immunogenic adeno-associated virus (the AAV9 vector) led to Cas9-specific CD8+-infiltrating T cells and humoral immunity without tissue cytolysis. Deep sequencing of the T-cell receptor Vβ revealed both common and unique Vβ Cas9-specific clonotypes5. These data suggested that the rational engineering of viral vectors may mitigate tissue damage from immune activation, and confirmed that the Cas9 protein itself was broadly immunogenic.

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Fig. 1: Potential methods for reducing immune responses to Cas9.

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Authors and Affiliations

  1. Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA

    Eric A. Wilson & Karen S. Anderson

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  1. Eric A. Wilson
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  2. Karen S. Anderson
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Correspondence to Karen S. Anderson.

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Competing interests

K.S.A. is noted as an inventor on a patent application regarding Cas9 immunity.

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Wilson, E.A., Anderson, K.S. Weakly immunogenic CRISPR therapies. Nat Biomed Eng 3, 761–762 (2019). https://doi.org/10.1038/s41551-019-0463-7

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  • DOI: https://doi.org/10.1038/s41551-019-0463-7

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