Inhibition of reverse transcription in type I interferon mediated neuropathology

Aicardi-Goutières综合征（AGS）是一种严重的儿童脑部疾病，与非常高水平的一种称为I型干扰素的化学物质有关。通常，我们只有在感染病毒时才会产生干扰素。在AGS中，没有明显的病毒感染。相反，由于这些个体的遗传密码（包含在我们的“DNA”中）发生了变化（突变），我们相信体内的细胞被愚弄了，认为这个人自己的DNA是病毒-也就是说，在区分“自我”和“非自我”时存在混淆。事实上，我们自己的大量DNA是由古老的病毒（“内源性逆转录病毒”）组成的，我们已经将其纳入我们的遗传物质数百万年-有时被称为“垃圾”DNA。这些内源性逆转录病毒仍然可以像来自体外的病毒一样发挥作用，因此需要对其进行控制。我们一直想知道，引起AGS的遗传变化是否意味着这些正常的控制机制不起作用。如果这是真的，内源性逆转录病毒将开始复制自己，这可以被我们的免疫系统识别为“外来”，导致干扰素的持续产生，然后破坏我们体内的细胞。由于我们不能修复每个细胞中的遗传密码，我们希望用逆转录酶抑制剂（RTIs）治疗AGS患者。RTIs用于对抗导致艾滋病的HIV-1病毒。在AGS的情况下，我们不是在治疗HIV-1，但我们想知道是否同样的药物可能能够控制内源性逆转录病毒，我们认为是驱动干扰素的生产。事实上，在最近完成的一项研究中使用这种治疗，我们收集了早期信息，表明我们确实看到患者的干扰素水平在一年内下降，当我们停止药物时，干扰素水平增加。此外，从科学的角度来看，这些研究对AGS患者及其家属具有巨大的潜在重要性。从科学的角度来看，如果研究结果支持垃圾DNA有时与人类疾病有关的可能性，我们的项目将引起相当大的兴趣。RTIs是一种非常安全的药物，已被世界各地数百万HIV-1感染者使用。如果我们的研究结果令人信服，我们相信它也值得考虑治疗其他疾病，这些疾病也被证明与I型干扰素水平升高有关，包括更常见的免疫疾病系统性红斑狼疮。

Aicardi-Goutières syndrome (AGS) is a severe childhood disease of the brain associated with very high levels of a chemical called type I interferon. Normally, we only produce interferon when we are infected with a virus. In AGS, there is no obvious viral infection. Instead, due to changes (mutations) in the genetic code (contained in our 'DNA') in these individuals, we believe that the cells in the body are fooled into thinking that the person's own DNA is viral - that is to say, there is a confusion in telling 'self' from 'non-self'. In fact, a large amount of our own DNA is made up of ancient virus ('endogenous retrovirus'), that we have taken into our genetic material over millions of years - sometimes referred to as 'junk' DNA. These endogenous retroviruses can still act like a virus coming from outside of the body, so that they need to be controlled. We have wondered if the genetic changes causing AGS mean that these normal control mechanisms don't work. If that was true, the endogenous retroviruses would start to make copies of themselves which could be recognised by our immune system as 'foreign', leading to the continuous production of interferon which then damages the cells in our body. Since we cannot repair the genetic code in every cell, we wish to treat AGS patients with drugs called reverse transcriptase inhibitors (RTIs). RTIs are used to fight the HIV-1 virus that causes AIDS. In the case of AGS, we are not treating HIV-1, but we wonder if the same drugs might be able to control endogenous retroviruses that we think are driving interferon production. Indeed, using this treatment in a recently completed study we gathered early information to suggest that we did see a reduction in interferon levels in patients over a one year period, with levels of interferon increasing when we stopped the drugs. Additionally, from a scientific point of view, these studies are of great potential importance for patients with AGS and their families. Scientifically, our project will be of considerable interest if the results support the possibility that junk DNA can sometimes be associated with human disease. RTIs are very safe drugs, that have been used in millions of people with HIV-1 around the world. If our results turn out to be convincing, we believe that it might also be worth thinking about treating other diseases that have also been shown to be associated with increased levels of type I interferon, including the much more common immune condition called systemic lupus erythematosus.