Reverse transcriptase inhibition as a novel therapeutic approach for ADAR-1-related Aicardi Goutières Syndrome

逆转录酶抑制作为 ADAR-1 相关 Aicardi Goutières 综合征的新型治疗方法

• 批准号: 10288270
• 负责人: Adeline Lucie Vanderver
• 金额: $ 49.96万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288270
• 关键词: Address; Adenosine; Affect; Alu Elements; Astrocytes; Biochemical; Biological Assay; Biological Models; Biology; Blood - brain barrier anatomy; Cell Death; Cell Line; Cells; Child; Clinical Research; Clinical Trials; DNA; Data; Defense Mechanisms; Double-Stranded RNA; Eligibility Determination; Embryo; Enrollment; Future; Genes; Genomics; Genotype; HIV Infections; Human; Immune response; Induced pluripotent stem cell derived neurons; Inflammatory; Inherited; Innate Immune System; Inosine; Interferon Activation; Interferons; Knockout Mice; Knowledge; Light; Link; Long Interspersed Elements; Measures; Mediating; Methods; Modeling; Molecular; Mutation; Natural Immunity; Neuraxis; Neurologic; Neurons; Neurosciences; Nucleic Acids; Outcome Measure; Pathologic; Pathology; Pathway interactions; Patients; Pediatric Hospitals; Philadelphia; Pilot Projects; Primates; RNA; RNA Processing; RNA-Directed DNA Polymerase; Regulation; Retroelements; Retrotransposition; Reverse Transcriptase Inhibitors; Role; Signal Transduction; Source; System; TREX1 gene; Tenofovir; Testing; Therapeutic; Transcript; Viral; Virus; Virus Diseases; Work; adenosine deaminase; autoinflammatory; base; cellular pathology; disability; disease-causing mutation; emtricitabine; follow-up; gene panel; imaging system; immune activation; improved; inclusion criteria; induced pluripotent stem cell; leukodystrophy; loss of function; mutant; nano-string; nervous system disorder; novel; novel therapeutic intervention; nucleic acid metabolism; patient population; pseudotoxoplasmosis syndrome; response; severe injury

Aicardi Goutières Syndrome (AGS) is an autoinflammatory leukodystrophy that results in severe neurologic disability along with systemic complications. AGS is caused by mutations in genes associated with DNA/RNA processing or intracellular sensing, leading to increased interferon response. While typically elicited due to a viral infection, in AGS these immune responses are triggered due to accumulation of endogenous nucleic acids such as retroelements. Retroelements, particularly LINE-1 is implicated in AGS caused due to mutations in TREX1, SAMHD1, RNASEH2A/B/C. But this association is not understood for mutations in the AGS genes IFIH1 and ADAR1. A prior pilot study shows that administration of reverse transcriptase inhibitor (RTI) can inhibit retroelement accumulation, decreasing activation of IFN pathways in AGS patients with TREX1, SAMHD1, RNASEH2A/B/C mutations. A follow-up clinical trial is being conducted at Children’s Hospital of Philadelphia (CHOP) as part of the Leukodystrophy Center of Excellence for the same patient population. However, ADAR1 patients (~14% of AGS patients) will be excluded from this study, as there is no evidence showing ADAR1 mutation leads to dysregulation of retroelements. This proposal will address this critical gap using human induced pluripotent stem cells (iPSC) derived from ADAR1 patients as a novel and relevant model system. Specifically, we will determine if ADAR1 mutations result in the dysregulation and accumulation of LINE-1 and Alu retroelements, which contributes to IFN-mediated cellular pathology in AGS (Aim1). We will further explore if treatment with RTI will be beneficial for ADAR1 mutation as observed for the other genotypes (Aim2) using molecular, biochemical and longitudinal survival assays. Our preliminary data show promising results and overall this proposal will combine our expertise in neuroscience and innate immunity to help shed light on the fundamental biology of a rare inherited leukodystrophy. The knowledge to be gained is also highly translational and immediately applicable to inclusion criteria for enrollment of AGS patients in the ongoing clinical trials at CHOP.

Aicardi Goutières 综合征 (AGS) 是一种自身炎症性脑白质营养不良，可导致严重的神经系统疾病 残疾以及全身并发症。 AGS 是由 DNA/RNA 相关基因突变引起的 处理或细胞内传感，导致干扰素反应增加。虽然通常是由病毒引起的 感染，在 AGS 中，这些免疫反应是由于内源核酸的积累而触发的，例如 作为复古元素。逆转录元件，特别是 LINE-1 与 TREX1 突变引起的 AGS 相关， SAMHD1、RNA酶H2A/B/C。但 AGS 基因 IFIH1 和 IFIH1 突变的这种关联尚不清楚。 ADAR1。先前的一项初步研究表明，使用逆转录酶抑制剂 (RTI) 可以抑制 逆转录元素积累，减少带有 TREX1、SAMHD1 的 AGS 患者 IFN 通路的激活， RNASEH2A/B/C 突变。后续临床试验正在费城儿童医院进行 (CHOP) 作为脑白质营养不良卓越中心的一部分，针对相同的患者群体。然而，ADAR1 患者（约 14% 的 AGS 患者）将被排除在本研究之外，因为没有证据表明 ADAR1 突变导致逆转录因子失调。该提案将利用人类诱导来解决这一关键差距 来自 ADAR1 患者的多能干细胞 (iPSC) 作为一种新颖且相关的模型系统。具体来说， 我们将确定 ADAR1 突变是否导致 LINE-1 和 Alu 的失调和积累 逆转录因子，有助于 AGS 中 IFN 介导的细胞病理学 (Aim1)。我们将进一步探讨是否 RTI 治疗将有利于 ADAR1 突变，正如使用其他基因型 (Aim2) 观察到的那样 分子、生化和纵向生存测定。我们的初步数据显示出有希望的结果和总体 该提案将结合我们在神经科学和先天免疫方面的专业知识，以帮助阐明 罕见遗传性脑白质营养不良的基础生物学。所获得的知识也是高度可转化的 并立即适用于正在进行的临床试验中 AGS 患者的纳入标准 劈。

项目成果

Generation of three induced pluripotent stem cell lines from individuals with Aicardi-Goutières syndrome caused by a c.3019G>A (p.G1007R) autosomal dominant pathogenic variant in ADAR1.

• DOI: 10.1016/j.scr.2023.103299
• 发表时间: 2024-02
• 期刊: STEM CELL RESEARCH
• 影响因子: 1.2
• 作者: Garcia, Luis;Gonzalez, Carlos Dominguez;Gagne, Alyssa;Mcguire, Jean Ann;French, Deborah;Takanohashi, Asako;Almad, Akshata;Vanderver, Adeline;Sase, Sunetra
• 通讯作者: Sase, Sunetra