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Translating nucleic acid-sensing pathways into therapies

Nature Reviews Immunology volume 15, pages 529–544 (2015)Cite this article

Subjects

Key Points

  • Endosomal and cytosolic nucleic acid receptors sense microbial nucleic acids and initiate innate immune responses. However, in some circumstances their activation by endogenous nucleic acids can also contribute to autoinflammation.

  • Nucleic acid sensors and their signalling pathways constitute promising drug targets for which synthetic oligonucleotide drugs as well as low-molecular-weight compounds are currently being developed.

  • Agonists of nucleic acid sensors function as immunostimulants and have uses in cancer immunotherapy or as vaccine adjuvants. The key challenge is to limit systemic inflammation.

  • Antagonists are being developed as immunomodulators for autoimmune diseases including systemic lupus erythematosus and psoriasis, and for autoinflammatory conditions (for example, type I interferonopathies). The key challenge is to design clinical proof-of-concept studies in which the pharmacological profile of antagonists is matched to the molecular phenotype of patients.

  • In vitro use of these compounds and results from animal studies as well as ongoing clinical trials are leading to a better molecular understanding of these indications. This, in turn, enables further drug discovery efforts for better therapy of diseases with high unmet medical need.

Abstract

Nucleic acid sensing by innate receptors initiates immune defences against viruses and other pathogens. A hallmark of this response is the release of interferons (IFNs), which promote protective immunity by inducing IFN-stimulated genes (ISGs). A similar ISG signature is found in autoinflammatory and autoimmune conditions, indicating that chronic activation of nucleic acid-sensing pathways may contribute to these diseases. Here, we review how nucleic acid-sensing pathways are currently being targeted pharmacologically with both agonists and antagonists. We discuss how an improved understanding of the biology of these pathways is leading to novel therapies for infections, cancer, and autoimmune and autoinflammatory disorders, and how new therapeutics will, in turn, generate a deeper understanding of these complex diseases.

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Figure 1: Endosomal and cytosolic nucleic acid-sensing pathways that provide pharmacological targets.
Figure 2: Access routes of self or foreign DNA and RNA to endosomes and to the cytosol.
Figure 3: Hypotheses about nucleic acid sensor activity and expression of the ISG signature over time in different physiological states.
Figure 4: Classification of interferon-associated inflammatory diseases.

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Acknowledgements

The authors thank E. Bartok, J. Deane, M. Hasan, P. Lötscher, D. Patel, A. Marshak-Rothstein and A. Weber for discussion and helpful suggestions relating to the manuscript.

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Authors and Affiliations

  1. Autoimmunity, Transplantation and Inflammation, Novartis Institute of Biomedical Research, Novartis Campus Forum 1, Basel, CH-4056, Switzerland

    Tobias Junt

  2. German Center for Infection Research Cologne–Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud Strasse 25, Bonn, 53127, Germany

    Winfried Barchet

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Correspondence to Tobias Junt.

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T.J. is an employee of Novartis Pharma, AG. W.B. declares no competing financial interests.

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Glossary

Pathophenotype

A disease subtype within a complex disease that is distinguished by certain clinical symptoms. Complex diseases such as systemic lupus erythematosus contain multiple pathophenotypes. The key challenge of molecular pathology is to match pathophenotypes to the activation of specific pathogenic pathways.

Antinuclear antibodies

(ANAs). Autoantibodies against double-stranded DNA or RNA-containing antigens (for example, Sjögren syndrome-related antigen A (SS-A; also known as Ro), SS-B (also known as La), Sm (spliceosomal) and small nuclear ribonucleoprotein 70 kDa (snRNP70)). Their presence in patient sera is a diagnostic hallmark of autoimmune diseases such as Sjögren syndrome and systemic lupus erythematosus. One diagnostic test for ANAs relies on specific staining pattern of cell nuclei with patient sera by immunofluorescence, hence the name.

Biomarkers

Measurable parameters that are reflective of specific biological processes in living organisms. Diagnostic biomarkers point to disease type or severity and may support patient stratification or selection. Pharmacodynamic biomarkers are measured in clinical trials to indicate pharmacological responses to compounds.

T cell-independent type 2 antigens

Polyvalent antigens that activate B cells by efficient crosslinking of the B cell receptor (BCR), without the need of T help. They differ from T cell-independent type 1 antigens, which are polyclonal B cell stimulants that activate B cells independently of BCR ligation.

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Junt, T., Barchet, W. Translating nucleic acid-sensing pathways into therapies. Nat Rev Immunol 15, 529–544 (2015). https://doi.org/10.1038/nri3875

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