Reverse Transcriptase Inhibitors in Aicardi Goutieres Syndrome

 描述（由申请方提供）：AGS是中枢神经系统病毒感染的遗传模拟物，伴有持续性脑脊液（CSF）细胞增多、CSF α干扰素（IFNa）、CSF新蝶呤/生物蝶呤升高和颅内钙化。通过鉴定与基因组监视、完整性和损伤修复相关的一系列基因（TREX 1、RNASEH 2 A/B/C、SAMHD 1、ADAR 1）中的突变，巩固了这种遗传性疾病的免疫基础。这些似乎导致细胞内RNA：DNA杂合体和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初始步骤是由LINE-1编码的逆转录酶驱动的免疫刺激性逆转录转座因子的积累引起的。在AGS模型中，用逆转录酶抑制剂（RTIs）治疗的小鼠数据显著降低了死亡率，这表明可能通过靶向宿主逆转录来中断这些免疫刺激核酸的产生。我们假设AGS表型是由逆转录因子衍生的转录本的积累引起的，导致免疫应答，其可以被逆转录酶抑制剂（RTI）中断。我们寻求弥合现有知识之间的差距，产生使用小鼠模型，我们的长期目标，有效的治疗。本研究的目的1是探索不同基因型AGS细胞中更广泛的逆转录因子类型和积累，从而探索内源性逆转录因子对疾病的贡献。一项先导试验，目标2，将提供安全性的证据和原则的证据，用于治疗AGS，一种毁灭性的，无法治疗的孤儿疾病，使用RTI，一组既定的药物。此外，目标3，我们将定义AGS中免疫激活的表型，以阐明逆转录因子积累对先天免疫的下游影响，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.