Reverse Transcriptase Inhibitors in Aicardi Goutieres Syndrome

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 DESCRIPTION (provided by applicant): Aicardi Goutieres Syndrome (AGS) is a genetic mimicker of viral infections of the central nervous system, with persistent cerebral spinal fluid (CSF) pleocytosis, elevated CSF alpha interferon (IFNa), CSF neopterin / biopterin and intracranial calcifications. The immune basis of this heritable disorder was solidified by the identification of mutations in a series of genes associated with genome surveillance, integrity and damage repair (TREX1, RNASEH2A/B/C, SAMHD1, ADAR1). These appear to result in the aberrant accumulation of RNA: DNA hybrids and other immunogenic nucleic acid structures within the cell. This suggests that the initial step in disease pathogenesis is caused by accumulation of immune-stimulatory retrotransposable elements driven by the LINE-1 encoded reverse transcriptase. Murine data, in which treatment with reverse-transcriptase inhibitors (RTIs) substantially reduced mortality in an AGS model, suggests it may be possible to interrupt the production of these immunostimulatory nucleic acids by targeting host reverse transcription. We hypothesize that the AGS phenotype is caused by accumulation of retroelement derived transcripts, resulting in an immune response, which can be interrupted by reverse transcriptase inhibitors (RTI). We seek to bridge the gap between current knowledge, generated using mouse models, and our long term goal of effective therapy. The propose research will explore the contribution of endogenous retroelements to disease by, Aim 1, exploring broader retroelement type and accumulation in AGS cells of different genotype. A pilot trial, Aim 2, will provide evidence of safety and proof of principle for treatment of AGS, a devastating, untreatable orphan disease, using RTI, an established group of pharmacologic agents. Additionally, Aim 3, we will define the phenotype of immune activation in AGS to clarify the downstream effect of retroelement accumulation on innate immunity and for use as potential biomarkers in future clinical trials.