Reverse Transcriptase Inhibitors in Aicardi Goutieres Syndrome

逆转录酶抑制剂治疗 Aicardi Goutieres 综合征

基本信息

批准号：
9378681
负责人：
William Allen Gahl
金额：
$ 16.43万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-17 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9378681
关键词：
ADAR1 Acute Aicardi&apos s syndrome Biological Markers Biopterin Blinded Blood Calcified Cells Central Nervous System Viral Diseases Cerebrospinal Fluid Child Childhood Clinical Clinical Treatment Clinical Trials Collaborations Consent Cross-Over Trials DNA Data Diphosphates Disease Disease Progression Elements Enrollment Experimental Designs Extramural Activities Future Genes Genetic Genetic Transcription Genome Genotype Goals Grant Hand Health system Heritability Human Hybrids Immune Immune response In Vitro Institutes Interferon Activation Interferon-alpha Interferons International Interruption Knowledge Leadership Letters Measures Mediating Mitochondria Modeling Monitor Mus Mutation Natural Immunity Neopterin Nucleic Acids Nucleotides Outcome Pathogenesis Patients Pharmaceutical Preparations Pharmacology Phase II Clinical Trials Phenotype Pleocytosis Principal Investigator Production Proteins Proteomics RNA RNA-Directed DNA Polymerase Rare Diseases Recruitment Activity Repetitive Sequence Research Research Personnel Research Priority Research Project Grants Resources Retroelements Reverse Transcriptase Inhibitors Reverse Transcription Safety Sampling Series Serum Surrogate Markers TREX1 gene Tenofovir Testing Toxic effect Transcript United States Food and Drug Administration United States National Institutes of Health autoinflammatory biobank calcification cytokine design efavirenz effective therapy emtricitabine immune activation immunogenic interest leukodystrophy mortality mouse model nervous system disorder nucleic acid structure nucleoside triphosphate pilot trial potential biomarker pseudotoxoplasmosis syndrome public health relevance repaired response response biomarker synergism treatment effect treatment response working group

ADAR1 Acute Aicardi&apos s syndrome Biological Markers Biopterin Blinded Blood Calcified Cells Central Nervous System Viral Diseases Cerebrospinal Fluid Child Childhood Clinical Clinical Treatment Clinical Trials Collaborations Consent Cross-Over Trials DNA Data Diphosphates Disease Disease Progression Elements Enrollment Experimental Designs Extramural Activities Future Genes Genetic Genetic Transcription Genome Genotype Goals Grant Hand Health system Heritability Human Hybrids Immune Immune response In Vitro Institutes Interferon Activation Interferon-alpha Interferons International Interruption Knowledge Leadership Letters Measures Mediating Mitochondria Modeling Monitor Mus Mutation Natural Immunity Neopterin Nucleic Acids Nucleotides Outcome Pathogenesis Patients Pharmaceutical Preparations Pharmacology Phase II Clinical Trials Phenotype Pleocytosis Principal Investigator Production Proteins Proteomics RNA RNA-Directed DNA Polymerase Rare Diseases Recruitment Activity Repetitive Sequence Research Research Personnel Research Priority Research Project Grants Resources Retroelements Reverse Transcriptase Inhibitors Reverse Transcription Safety Sampling Series Serum Surrogate Markers TREX1 gene Tenofovir Testing Toxic effect Transcript United States Food and Drug Administration United States National Institutes of Health autoinflammatory biobank calcification cytokine design efavirenz effective therapy emtricitabine immune activation immunogenic interest leukodystrophy mortality mouse model nervous system disorder nucleic acid structure nucleoside triphosphate pilot trial potential biomarker pseudotoxoplasmosis syndrome public health relevance repaired response response biomarker synergism treatment effect treatment response working group

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项目摘要

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.

描述（由适用提供）：Aicardi Goutieres综合征（AGS）是中枢神经系统病毒感染的遗传模仿者，具有持续的脑脊髓液（CSF）多细胞增多症，CSF Alpha Interferon（IFNA），CSF肾上腺素 /生物蛋白酶替代和含量calctionication concsf升高。通过鉴定与基因组监测，完整性和损伤修复相关的一系列基因中的突变（TREX1，RNASEH2A/B/C，SAMHD1，ADAR1）的一系列基因中的突变鉴定来巩固这种遗传障碍的免疫力。这些似乎导致RNA的异常积累：DNA杂种和细胞内的其他免疫原性结构。这表明，疾病发病机理的第一步是由由线1编码的逆转录酶驱动的免疫刺激反转介元素的积累引起的。在AGS模型中，用反向转移酶抑制剂（RTI）处理的鼠数据大大降低了死亡率，这表明可以通过靶向宿主逆转录来中断这些免疫刺激性核酸的产生。我们假设AG表型是由逆转录转录物的积累引起的，导致免疫反应，可以被逆转录酶抑制剂（RTI）中断。我们试图弥合当前知识，使用小鼠模型产生的差距，以及我们有效治疗的长期目标。该提案研究将通过AIM 1，Explorer retroement类型和不同基因型的AGS细胞中的探索者重新元素类型和积累来探讨内源性逆转元素对疾病的贡献。 AIM 2的初步试验将提供安全和原理证明AGS的证据，这是一种毁灭性的，不可治疗的孤儿疾病，使用RTI（已建立的一组药物剂RTI）。此外，AIM 3，我们将定义AG中免疫反应的表型，以阐明恢复积累对先天免疫学的下游影响，并用作未来临床试验的潜在生物标志物。