Abstract
The dichotomic nature of the adaptive immune response governs the outcome of clinical gene therapy. On the one hand, neutralizing antibodies and cytotoxic T cells can have a dramatic impact on the efficacy and safety of human gene therapies. On the other hand, regulatory T cells (Treg) can promote tolerance toward transgenes thereby enabling long-term benefits of in vivo gene therapy after a single administration. Pre-existing antibodies and T cell immunity has been a major obstacle for in vivo gene therapies with viral vectors. As CRISPR-Cas9 gene editing advances toward the clinics, the technology’s inherent immunogenicity must be addressed in order to guide clinical treatment decisions. This review summarizes the recent evidence on Cas9-specific immunity in humans—including early results from clinical trials—and discusses the risks for in vivo gene therapies. Finally, we focus on solutions and highlight the potential role of Cas9-specific Treg cells to promote immune tolerance. As a “beneficial alliance” beyond Cas9-immunity, antigen-specific Treg cells may serve as a living and targeted immunosuppressant to increase safety and efficacy of gene therapy.
Highlights
Immune tolerance to transgenes and vector components are associated with longterm transgene expression and clinical success in some trials [2, 3]
In muscle-directed AAV therapy, Gernoux et al showed that long-term transgene expression is associated with the simultaneous infiltration of Treg cells into the muscle and the exhaustion of Teff [6]
Treg cells are a multifunctional immunosuppressive cell type implicated in the control of overshooting immune responses and tissue regeneration
Summary
The interaction between the immune system and gene therapeutic agents in vivo largely determines long-term benefit of the treatment intervention [1]. A growing body of evidence highlights the importance of transgene- and vector-specific Treg cells for successful long-term benefits of in vivo gene therapy in animal models and humans The role and potential of preexisting antigen-specific Treg cells for gene therapy has not been intensively studied in humans.
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