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Every project supported by Gebert Rüf Stiftung is made accessible with a web presentation that informs about the core data of the project. With this public presentation, the foundation publishes the funding results achieved and contributes to the communication of science to society.

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Novel treatment options for Aicardi-Goutières Syndrome (AGS) – Rare Diseases 2014

Editorial

Für den Inhalt der Angaben zeichnet die Projektleitung verantwortlich.

Cooperation

This project is one of the five winners of the call 2014 «Rare Diseases - New Approaches». Project partners: Ecole Polytechnique Fédérale de Lausanne, EPFL

Project data

  • Project no: GRS-059/14 
  • Amount of funding: CHF 470000 
  • Approved: 06.11.2014 
  • Duration: 04.2015 - 06.2019 
  • Area of activity:  Rare Diseases, 2009 - 2014

Project management

Project description

Aicardi-Goutières Syndrome (AGS) is a genetically determined autoimmune disease. The clinical features of AGS mimic those of in utero viral infection and predominantly involve severe neurological dysfunctions that manifests in early childhood. These symptoms arise due to unabated overproduction of type I interferons, a class of cytokines, which physiologically serve important functions in the innate immune response against viruses. Today we know that defects in distinct nucleic acid metabolizing enzyme are associated with AGS, which lead to the erroneous accumulation of self DNA and self RNA in the cytosol of cells. As a consequence of this nucleic acid sensors of the innate immune system are activated and lead to the production of type I IFNs. Currently, there is no treatment for AGS available.

Our previous work has revealed that in cells that are defective in the AGS-associated gene TREX1 accumulation of self DNA stimulates the cytosolic DNA receptor cyclic GAMP synthase (cGAS). On the basis of this study it is the goal of this project to further characterized the molecular mechanism that connects the activation of cGAS with the induction of type I IFNs and in particular to identify small molecule compounds that interfere with the activation of the cGAS-triggered signaling pathway.

What is special about the project?

Currently, beyond the supportive management of the chronic neurological symptoms, a standard treatment for AGS is not available and 40% of affected patients die in early childhood. In this context an important aspect to be noted is, that little disease progression seems to occur beyond the initial disease episode. Thus, an intervention that is effective during the initial period of the disease holds great promise to be effective in the attenuation of the consecutive tissue insults and also the overall disease outcome. The goal of our research project is to delineate the missing link between the accumulation of DNA and activation of cGAS. Moreover, we aim to test whether targeting the disease at its most proximal step – the recognition of self DNA by cGAS - can serve to guide the development of novel treatment opportunities for AGS.

Status/Results

The research project “AGS and NA sensing” resulted in a better understanding of how innate sensing of self-DNA contributes to pathophysiological inflammatory responses. Specifically, we found that cGAS responds to self-DNA accumulating within senescent cells. Activation of cGAS, in turn, promotes the secretion of cytokines and chemokines and, thereby, contributes to establish the inflammatory state of senescent cells. In addition, we have identified small molecule inhibitors of STING. Through studying their mechanism of action, we found that the compounds bind STING in a covalent manner, block STING palmitoylation, and downstream signaling activity. The compounds were efficacious in a mouse model of AGS, thus providing the first proof-of-concept study that pharmacological intervention into STING may be beneficial for the treatment of autoinflammatory disease.

Publications

Simone M. Haag, Muhammet F. Gulen, Luc Reymond, Antoine Gibelin, Laurence Abrami, Alexiane Decout, Michael Heymann, F. Gisou van der Goot, Gerardo Turcatti, Rayk Behrendt and Andrea Ablasser. Targeting STING with covalent small-molecule inhibitors. 12 July 2018, Vol. 559, Nature
Selene Glück, Baptiste Guey, Muhammet Fatih Gulen, Katharina Wolter, Tae-Won Kang, Niklas Arndt Schmacke, Anne Bridgeman, Jan Rehwinkel, Lars Zender and Andrea Ablasser. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nature Cell Biology, June 2017;
Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V. TREX1-deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. Journal of Immunology. 2014 Jun 15;192(12):5993-7.

Links

Persons involved in the project

Prof. Dr. Andrea Ablasser, Projektleiterin

Last update to this project presentation  06.03.2023