Investigating mitochondrial alterations as novel therapeutic targets for the Aicardi-Goutières Syndrome

From bacteria to vertebrates, life has established sophisticated mechanisms to detect, restrict and eliminate foreign genetic material. It has become increasingly apparent that these same mechanisms that protect us from viral infection can also drive specific human diseases when they are inappropriately activated. This type of aberrant activation of immune responses has been suggested to be a primary driver of pathogenesis of the Aicardi-Goutières Syndrome (AGS), a genetic Leukodystrophy that mainly affects the brain, immune system and skin. Nevertheless, why cells in AGS activate these immune responses without microbial infection is still unknown, as it has been difficult thus far to recapitulate the disease in experimental models. Our approach is based on a novel technology that exploits induced pluripotent stem cells (iPSC), which allow us to faithfully model the disease from a developmental point of view. This iPSC-based strategy has already proven successful to uncover some aspects of AGS-related neurotoxicity. Here we will focus our attention on identifying what are the endogenous molecules that aberrantly activate the disease-causing antiviral responses in these cells and dissecting how AGS causing genes lead to the presence of these triggers in AGS cells. 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 and other deadly leukodystrophies.