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

Aicardi Gtières综合征(AGS)是一种导致严重神经功能障碍的自体炎症性脑白质营养不良 残疾和全身并发症。AGS是由与DNA/RNA相关的基因突变引起的 加工或细胞内感应，导致干扰素反应增强。虽然通常是由于病毒引起的 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，如 作为逆行元素。逆转录元件，特别是LINE-1与TREX1突变引起的AGs有关， SAMHD1、RNASEH2 A/B/C，但这种关联对于AGS基因IFIH1和 ADAR1.先前的一项初步研究表明，给予逆转录酶抑制剂(RTI)可以抑制 AGS患者TREX1、SAMHD1、TREX1、SAMHD1逆转录因子积聚、干扰素途径激活减少 RNASH_2A/B/C突变。费城儿童医院正在进行后续临床试验 (CHOP)作为针对相同患者群体的脑白质营养不良卓越中心的一部分。然而，ADAR1 患者(约14%的AGS患者)将被排除在这项研究之外，因为没有证据表明ADAR1 突变会导致逆转录元件的失调。该提案将使用人工诱导来解决这一关键差距 ADAR1患者来源的多能干细胞(IPSC)作为一种新的相关模型系统。具体来说， 我们将确定ADAR1突变是否导致Line-1和Alu的失调和堆积 逆转录元件，这有助于干扰素介导的AGS(Aim1)的细胞病理。我们将进一步探讨是否 用RTI治疗将有益于ADAR1突变，正如在使用 分子、生化和纵向生存分析。我们的初步数据显示了令人振奋的结果，总体来说 这项提议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 一种罕见遗传性脑白质营养不良的基础生物学。要获得的知识也是高度可翻译的 并立即适用于正在进行的临床试验中登记AGS患者的纳入标准 砍吧。

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.