New therapeutic concepts for NIMBL disorders
NIMBL conditions include the Aicardi-Goutieres syndrome (AGS), retinal vasculopathy with cerebral leukodystrophy (RVCL) and some cases of systemic lupus erythematosus. Collectively, patients with these genetic disorders suffer from low quality of life and high mortality. To enable optimum patient care, the EU-funded (NIMBL) (Nuclease immune mediated brain and lupus-like conditions (NIMBL): natural history, pathophysiology, diagnostic and therapeutic modalities with application to other disorders of autoimmunity) project has provided a better understanding of the natural course of these disorders and their underlying pathological basis. Project achievements include data collection from 346 affected individuals belonging to 277 families with a confirmed molecular diagnosis of AGS, and 78 RVCL TREX1 mutation-positive patients. This represents the largest set of clinical and molecular information ever collected for these rare conditions. The consortium built on very recent discoveries in autoimmunity and a new biological paradigm involving cytosolic sensors that detect accumulated, endogenous nucleic acids and induce the body to mount an immune response against self. NIMBL researchers studied the genetic basis of these disorders by defining their mutational spectrum. Highlights of this work include the identification of mutations in two new disease-associated genes, ADAR1 and IFIH1. To explore the origins and progression of autoimmune disease in NIMBL-related disorders, project scientists used disease mouse models. Tracking of disease initiation in Trex1-deficient mice revealed interferon production by non-haematopoietic cells. NIMBL researchers have elucidated this mechanism of autoimmunity involving the inappropriate activation of nucleic acid sensors. The importance of type I interferons in the pathology of AGS has been highlighted, which strongly implicates the defective control of retroelement metabolism in AGS biology, a novel concept. The NIMBL project has proven of immediate benefit for patients through improved diagnostics and significantly enhanced clinical knowledge of NIMBL-associated conditions. Moreover, it is hoped that the advances in molecular knowledge underlying these conditions will have profound ramifications for the development of future therapies.
Keywords
NIMBL disorders, autoimmunity, mutations, mouse model, interferons
