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

描述(由申请人提供)：有快速增长的艾滋病毒文献，它已经发现了一套遗传的遗传差异，可以预测：a)部分感染人群谁将进展缓慢，或永远不会进展到艾滋病症状(所谓的精英控制者)，或b)部分感染人口谁将发展剂量限制，史蒂文斯-约翰逊一样的炎症反应阿巴卡韦，因此，不能给予的第一级艾滋病抗逆转录病毒。文献表明，这两种影响都集中在人类白细胞抗原B基因座的个人化变异上。事实上，许多人现在认为，人类白细胞抗原-B在阿巴卡韦过敏和“精英控制者”对艾滋病的抵抗中所起的作用是整个个性化药物领域的黄金标准。基于人类白细胞抗原-B在个人化医学、艾滋病以及史蒂文斯-约翰逊综合征和反应性关节炎(加上目前更具推测性的许多其他疾病)中的作用迅速扩大，我们认为现在是时候开发一种简单、低成本、一次性的基因测试，用于分析所有与艾滋病相关的人类白细胞抗原-B基因变异，并着眼于未来将这种人类白细胞抗原-B测试扩展到个性化医学中的新适应症。在这项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，称为“艾滋病芯片”，它将作为一种单一、简单、廉价、紧凑的微阵列测试来执行非常高分辨率的HLA-B测试。这项测试将以一种可以扩展为更广泛适用的基于HLA-B的疾病风险和药物反应的测试方法来衡量艾滋病进展和治疗反应的遗传因素，这种方法以后可以扩展到更广泛适用的医学领域，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被高度冗余。它可以包含辅助基因，如KIR和CCR5，更重要的是，它可以与高通量、干燥状态的Guthie卡样本采集相结合，在第二阶段，将自然适合作为低成本、ASHI验证的实验室过程和FDA批准的510K IVD来开发AIDS-Chip。与公共卫生相关：至少20年来，对免疫系统的基本了解要求，人类白细胞抗原基因簇的个性化变异，特别是I型人类白细胞抗原基因，必须在对感染的反应中引起某种个性化变异。然而，当时的工具不足以足够详细地发现这种(预测的)相关性而不是有用的，也不足以将这些信息部署在现场作为公共健康测试。然而，基于应用遗传学工具的最新进展，在疾病严重性的推动下，这种明确的人类白细胞抗原与艾滋病的相关性已经出现，并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群规模上应用基因测试方法进行基于人类白细胞抗原的疾病风险分析的时代。我们认为，HIV-AIDS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身变异。这项SBIR将开发的技术将有助于提供这些新发现的人类白细胞抗原-艾滋病相关性，作为一种低成本、基于人群的基因测试。然而，也许更重要的是，我们将开发的技术平台(复杂的基因测试干燥状态样本收集)将被历史上视为未来几十年人口规模遗传学将用于所有疾病的模式。毫无疑问，十年后，将出现比我们将在这里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，无论这些新的种群规模的基因工具是什么，它们的使用方式都将看起来非常像这种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.