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

AGS综合征是一种自身炎症性脑白质营养不良， 残疾沿着全身并发症。AGS是由与DNA/RNA相关的基因突变引起的 加工或细胞内感应，导致干扰素应答增加。虽然通常是由病毒引起的， 感染，在AGS中，这些免疫应答由于内源性核酸的积累而被触发， 作为复古元素。逆转录因子，特别是LINE-1与TREX 1突变引起的AGS有关， SAMHD 1、RNASEH 2 A/B/C。但是，AGS基因IFIH 1和IFIH 2突变的这种关联尚不清楚。 ADAR 1.先前的初步研究表明，逆转录酶抑制剂（RTI）的管理可以抑制 逆转录因子的积累，减少AGS患者的IFN途径的活化，TREX 1，SAMHD 1， RNASEH 2 A/B/C突变。费城儿童医院正在进行一项后续临床试验 （CHOP）作为脑白质营养不良卓越中心的一部分，用于相同的患者人群。ADAR1 患者（约14%的AGS患者）将从本研究中排除，因为没有证据显示ADAR 1 突变导致逆转录因子的失调。该提案将利用人类诱导的 多能干细胞（iPSC）来源于ADAR 1患者作为一种新的和相关的模型系统。具体地说， 我们将确定ADAR 1突变是否导致LINE-1和Alu的失调和积累， 逆转录因子，这有助于AGS（Aim 1）中IFN介导的细胞病理学。我们将进一步探讨， RTI治疗将有利于ADAR 1突变，如使用RT-PCR对其他基因型（Aim 2）观察到的那样。 分子、生物化学和纵向存活测定。我们的初步数据显示， 这项提案将联合收割机结合我们在神经科学和先天免疫方面的专业知识， 一种罕见的遗传性脑白质营养不良的基础生物学获得的知识也是高度翻译的 并立即适用于正在进行的临床试验中AGS患者入组的入选标准， 快点

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.