The Aicardi-Goutières Syndrome – From nucleic acid sensing to disease modeling

Deregulation of cell intrinsic pathways of nucleic acid sensing is emerging as a potential driver of several autoinflammatory and autoimmune diseases. Among these, aberrant sensing of nucleic acids originating from the expression of endogenous retroviral elements (ERE) or accumulating DNA damage and consequent increase in type I IFN levels have been suggested to be a primary driver of pathogenesis of the Aicardi-Goutières Syndrome (AGS). AGS is a rare monogenic inflammatory encephalopathy that can be caused by mutations in any one of seven genes encoding for proteins involved in the metabolism/processing of RNA/DNA. Nevertheless, the precise molecular mechanisms triggering disease remain elusive due to the lack of viable animal models recapitulating the human neuropathology and thus far few molecular studies conducted in physiologically relevant cell types. On these premises, we are investigating the cell intrinsic consequences AGS mutations using iPSC, in which we have mimicked loss of AGS genes. These iPSC can then be in vitro differentiated into neural progenitors such as astrocytes and neurons to study functional consequences of AGS gene defects and identify what is triggering them. Determining precisely how, where and when the pathological innate sensing cascade is initiated in AGS will provide critical knowledge for the development of targeted therapies to prevent onset and progression of this deadly disease.