**4. Conclusion: Plasmid DNA as a promising immunotherapy for Type 1 diabetes**

Plasmid DNA is a versatile vector platform permitting the seamless integration of different immune modulators into a product that can be manufactured in a generic manner. As we have seen in this chapter, plasmid DNA has been extensively investigated for the prevention and treatment of type 1 diabetes in different animal model systems. Plasmid DNA-based gene immunotherapies do not encode an autoantigen and act systemically to different degrees, which could result in serious adverse events if used over time. Nevertheless, gene immuno‐ therapies could still be utilized as molecular adjuvants with DNA vaccines that target pan‐ creatic beta cell autoantigens. It is possible that different stages during progression of disease will require different therapeutic agents or combinations thereof according to immune responses to therapy. It is also anticipated that some strategies will be safer and more robust than others, but there is unfortunately no animal model that can predict successful bench-tobedside translation of a given strategy. In that regard, immunological biomarkers and their pre-clinical and clinical correlates will be needed to determine which strategies are most likely to be effective in humans, and to what extent different immunotherapies might be combined. Combinatorial therapies include co-delivery of DNA vaccines with gene therapy, peptide vaccines, monoclonal antibodies, and other adjuvant agents that have shown synergistic effects. In one possible scenario, autoantigen-specific immunotherapies could be used over the long-term as stand-alone treatments, with the occasional help of systemic immune modulators depending on disease severity. Regardless of the strategy to be chosen, there is a strong case to be made for including plasmid DNA immunotherapy in future treatments of type 1 diabetes.

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