A Low Cost Microarray for Population-Scale AIDS Risk Analysis: The AIDS Chip

描述（由申请人提供）：关于HIV的文献越来越多，发现了一组遗传基因差异，可以预测：a)感染人群中进展缓慢或从未出现艾滋病症状的部分（所谓的精英控制者），或b)感染人群中对阿巴卡韦产生剂量限制、史蒂文斯-约翰逊样炎症反应的部分，因此不能给予第一线艾滋病抗逆转录病毒治疗。文献表明，这两种影响都集中在HLA-B位点的个性化变异上。事实上，许多人现在认为，HLA-B在阿巴卡韦过敏和“精英控制者”抗艾滋病中的作用是整个个性化医疗领域的黄金标准。基于这个快速扩张作用HLA-B个性化医疗、艾滋病和史蒂文斯—约翰逊综合征等条件与反应性关节炎(加上许多人更投机目前),我们认为现在是时候开发一个简单的、低成本、锅基因测试可以用来分析所有AIDS-relevant HLA-B遗传变异,用未来的眼光来扩展这种HLA-B测试包含个性化医疗的新迹象,。在这个SBIR中，我们将使用我们发明的一种新的微阵列技术来开发一种专门的，非常低成本的微阵列测试，被称为“艾滋病芯片”，它将执行非常高分辨率的HLA-B测试，作为一个单一的，简单的，廉价的，紧凑的微阵列测试。该测试将测量艾滋病进展的遗传因素和HLA-B基因座内体现的治疗反应，这种方法可以扩展为一种更广泛适用的基于HLA-B的疾病风险和药物反应测试，在医学领域可能远远超出本SBIR的艾滋病重点。我们的艾滋病芯片的一个关键组成部分是，它可以高度冗余。它可以包含辅助基因，如KIR和CCR5，重要的是，它可以耦合到Guthrie卡上的高通量、干态样本采集，在II期，它将自然适合开发艾滋病芯片，作为低成本的、经过ashi验证的实验室工艺，并与FDA一起，作为510K批准的IVD。公共卫生相关性：至少20年来，对免疫系统的基本了解要求HLA基因簇的个体化变异，特别是I型HLA基因，必须引起对感染反应的某种个体化变异。然而，当时的工具还不足以充分详细地发现这种（预测的）相关性，使之有用，也不足以在实地部署这些信息，作为公共卫生测试。然而，基于应用遗传学工具的最新进展，以及疾病的严重程度，这种明确的HLA相关性已经出现在艾滋病中，并已成为该领域主要兴奋的基础。因此，正如多年来所预测的那样，我们现在正在进入一个可以在人口规模上应用基因检测方法进行基于hla的疾病风险分析的时代。我们认为，hiv -艾滋病将被视为许多此类疾病中的第一种，在这些疾病中，可遗传的HLA变异可以帮助预测疾病风险的终生变化。在这个SBIR中开发的技术将有助于提供新发现的HLA-AIDS相关性，作为一种低成本的、基于人群的基因检测。然而，也许更重要的是，我们将开发的技术平台（复杂的基因测试+干态样本收集）将被历史地视为一种模式，在未来几十年里，群体规模的遗传学将被用于所有疾病。毫无疑问，十年后，将会出现比我们现在开发的艾滋病芯片更好、更快、更便宜的新技术。然而，我们同样可以肯定的是，无论这些新的人口规模基因工具是什么，它们的使用方式将非常像这个SBIR的“格思里卡+艾滋病芯片”配对。

DESCRIPTION (provided by applicant): There is rapidly growing HIV literature, which has discovered a set of inherited genetic differences which can predict: a) the fraction of an infected population who will progress slowly, or never progress to AIDS symptoms (the so-called Elite Controllers), or b) the fraction of an infected population who will develop a dose limiting, Stevens-Johnson like inflammatory response to abacavir, and consequently, cannot be given that first-tier AIDS antiretroviral. The literature suggests that both of those effects are centered upon personalized variation within the HLA-B locus. Indeed, many now view the role of HLA-B in abacavir hypersensitivity and "Elite Controller" resistance to AIDS to be the gold standard for the entire field of personalized medicine. Based on this rapidly expanding role for HLA-B in personalized medicine, for AIDS and for conditions such as Stevens-Johnson syndrome & reactive arthritis (plus many others that are more speculative at present), we argue that the time is right to develop a simple, low-cost, one-pot genetic test which can be used for the analysis of all AIDS-relevant genetic variation in HLA-B, with a future eye to extending such HLA-B testing to encompass new indications in personalized medicine, as well. In this SBIR, we will use a novel microarray technology that we have invented to develop a specialized, very low cost microarray test, referred to as the "AIDS-Chip," which will perform very-high-resolution HLA-B testing as a single, simple, inexpensive, compact microarray test. This test will measure genetic factors of AIDS progression and therapeutic response embodied within the HLA-B locus in a way that can be expanded, later, into a more broadly-applicable HLA-B-based test for disease risk & pharmaceutical response in areas of medicine that might extend far beyond the AIDS focus of this SBIR. A key component of our AIDS-Chip is that it can be made highly redundant. It can encompass auxiliary genes such as KIR and CCR5, and importantly, can be coupled to high throughput, dry state sample collection on Guthrie cards in a way that, in Phase II, will be naturally suited for development of the AIDS-Chip as a low cost, ASHI-validated laboratory process and, with the FDA, as a 510K approved IVD. PUBLIC HEALTH RELEVANCE: For at least twenty years, a basic understanding of the immune system would have required that personalized variation in the HLA gene cluster, especially Type I HLA genes, must give rise to some sort of personalized variation in the response to infection. However, the tools of the day were not sufficient to discover such (predicted) correlations in enough detail to be useful, nor to deploy that information in the field, as a public health test. However, based upon recent advancements in the tools of applied genetics, and driven by the severity of the disease, such explicit HLA correlations have emerged for AIDS and have been the basis for major excitement in the field. Thus, as had been predicted for many years, we are now entering an era where the methods of genetic testing can be applied, at the population scale, for HLA-based disease risk analysis. We argue that HIV-AIDS will be viewed as only the first of many such diseases, where heritable HLA variation can help predict life-long variation in disease risk. The technology to be developed in this SBIR will help deliver those newly discovered HLA-AIDS correlations, as a low-cost, population based genetic test. However, perhaps more importantly, a technology platform such as that which we will develop (a complex genetic test + dry state sample collection) will be viewed historically as a model for the way that population scale genetics will be used for all diseases in the decades to come. There is no doubt that, ten years from now, new technologies will emerge that are better, faster & cheaper than the AIDS-Chip that we will develop here. However, we are equally certain that, whatever those new population scale genetic tools may be, the way that they are used, will look very much like the "Guthrie Card + AIDS-Chip" pairing of this SBIR.