Antiretroviral Therapy in Aicardi Goutieres Syndrome

 描述(申请人提供)：Aicardi Goutieres综合征(AGS)是一种中枢神经系统病毒感染的遗传模仿者，伴有持续性脑脊液(CSF)细胞增多、脑脊液α干扰素(IFNA)升高、脑脊液新喋呤/生物蝶呤和颅内钙化。这种遗传性疾病的免疫基础通过一系列与基因组监测、完整性和损伤修复相关的基因突变(TREX1、RNASEH2 A/B/C、SAMHD1、ADAR1)的鉴定而得到巩固。这些似乎导致RNA：DNA杂交体和细胞内其他免疫原性核酸结构的异常积累。这表明疾病发病机制的最初步骤是由LINE-1编码的逆转录酶驱动的免疫刺激逆转座元件的积累引起的。在AGS模型中，用逆转录酶抑制剂(RTI)治疗显著降低死亡率的小鼠数据表明，通过靶向宿主反转录来中断这些免疫刺激核酸的产生是可能的。我们假设AGS的表型是由逆转录元件衍生的转录本的积累引起的，导致免疫反应，这可以被逆转录酶抑制物(RTI)中断。我们寻求弥合目前利用小鼠模型产生的知识与我们有效治疗的长期目标之间的差距。本研究将探索内源性逆转录元件在疾病中的作用，目的1，探索不同基因类型的AGS细胞中更广泛的逆转录元件类型和积累。一项名为AIM 2的试点试验将提供使用RTI治疗AGS的安全性证据和原则证明。AGS是一种毁灭性的、无法治疗的孤儿疾病，RTI是一组既定的药理药物。此外，目标3，我们将定义AGS中免疫激活的表型，以阐明逆转录元件积累对天然免疫的下游影响，并在未来的临床试验中用作潜在的生物标志物。

 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.