Research projects

AAicardi-Goutières Syndrome (AGS) is a severe rare hereditary disease. It causes a progressive neurodegeneration that strongly compromises the survival of the patients. It is a monogenic autosomic disorder, but of heterogenic etiology. In fact, there are 9 known genes which mutations can cause AGS. At the molecular level, AGS is believed to be dependent on an interferon-mediated autoimmune response towards specific aberrant nucleic acid structures that accumulate on those individuals bearing AGS mutations. Previous published and unpublished results from our lab connected AGS genes with the repair of DNA double strand breaks. Thus, we proposed to study the connection between AGS-causing mutations and this process, but also the connection with the interferon pathway. We have shown that not only all AGS-related mutations impair DNA repair, but also that such defect is mediated by an aberrant elimination of DNA:RNA hybrids. 

Furthermore, we have seen that different treatments that were proposed to reduce interferon on those patients were able to rescue the defective DNA repair at the cellular level, suggesting that is the interferon activation what blocks DNA repair and not the other way around. Also, we have taken the inverse approach and search for drugs that rescue the hampered DNA repair in patients-derived cells. Between them, at least one is able to reduce the cellular interferon levels in AGS cellular models, thus suggesting they can be used as palliative treatments in the patients. This open a new research avenue to search for therapeutic interventions for this devastating disease.