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

用于人口规模艾滋病风险分析的低成本微阵列：艾滋病芯片

• 批准号: 7755340
• 负责人: MICHAEL E. HOGAN
• 金额: $ 30万
• 依托单位: GENOMICS USA, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755340
• 关键词: Accounting; Accreditation; Acquired Immunodeficiency Syndrome; Adult; Alleles; Anti-Retroviral Agents; Applied Genetics; Area; Arizona; Automation; Blood; Blood specimen; CCL3L1 gene; CCR5 gene; Certification; Clinic; Clinical; Collaborations; Collection; Complex; Computer software; Coupled; Coupling; DNA; DNA analysis; Data; Databases; Development; Diagnostic; Digit structure; Disease; Dose-Limiting; Drops; Elements; Ensure; Epidemiology; Evaluation; Event; Eye; Family; Fingers; Freezing; Future; Gene Cluster; Genes; Genetic; Genetic Variation; Genetic screening method; Genomics; Goals; Gold; HIV; HLA-A gene; HLA-B Antigens; Home environment; Hypersensitivity; Immune system; Immunogenetics; Individual; Infection; Inflammatory Response; Inherited; Ink; International; Knowledge; Laboratories; Letters; Life; Liquid substance; Literature; Marketing; Measurable; Measures; Medical; Medicine; Methods; Microarray Analysis; Microscope; Modeling; Monitor; New Zealand; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pilot Projects; Play; Ploidies; Population; Price; Printing; Process; Production; Protocols documentation; Public Health; Reaction; Reactive Arthritis; Reagent; Recovery; Reference Standards; Relative (related person); Research Ethics Committees; Resistance; Resolution; Risk; Role; Running; Sampling; Services; Severity of illness; Site; Slide; Small Business Innovation Research Grant; Solutions; Sorting - Cell Movement; Specimen; Spottings; Stevens-Johnson Syndrome; Structure; Symptoms; Technology; Testing; Therapeutic; Time; Uncertainty; Universities; Validation; Variant; Work; abacavir; base; cost; design; disorder risk; field study; human leukocyte antigen gene; interest; kamala; magnetic beads; manufacturing scale-up; meetings; new technology; novel; population based; prototype; public health relevance; research and development; research clinical testing; response; sample collection; scale up; theories; tool

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.

描述（申请人提供）：艾滋病毒文献迅速增加，发现了一系列遗传性遗传差异，可以预测：a）受感染人口中进展缓慢或永远不会出现艾滋病症状的比例（所谓的精英控制者），或B）将对阿巴卡韦产生剂量限制性Stevens-Johnson样炎症反应的感染人群的一部分，因此，不能给予第一级艾滋病抗逆转录病毒药物。文献表明，这两种效应都集中在HLA-B基因座内的个性化变异上。事实上，许多人现在认为HLA-B在阿巴卡韦超敏反应和“精英控制者”对艾滋病的抵抗中的作用是整个个性化医疗领域的黄金标准。基于HLA-B在个性化医疗、艾滋病以及Stevens-Johnson综合征和反应性关节炎等疾病中的作用迅速扩大，（加上许多其他目前更具投机性的），我们认为，现在是时候开发一种简单，低成本，一锅基因测试，可用于分析HLA-B中所有艾滋病相关的遗传变异，未来的目光将扩展这种HLA-B测试，以涵盖个性化医疗的新适应症。在这个SBIR中，我们将使用一种新的微阵列技术，我们已经发明了开发一个专门的，非常低成本的微阵列测试，被称为“艾滋病芯片”，这将执行非常高的分辨率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，其方式可以扩展到更广泛适用的基于HLA-B的疾病风险和药物反应测试，这些测试可能远远超出该SBIR的艾滋病焦点。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。它可以包括辅助基因，如KIR和CCR 5，并且重要的是，可以与古特里卡上的高通量、干燥状态样品收集相结合，在第二阶段，这种结合将自然地适合于开发作为低成本、ASHI验证的实验室方法的AIDS-芯片，并且作为FDA批准的510 K 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（尤其是I型HLA基因）中的个性化变异必须在对感染的反应中引起某种个性化变异。然而，当时的工具不足以发现这种（预测的）相关性，也不足以将这些信息部署在现场，作为公共卫生测试。然而，基于应用遗传学工具的最新进展，并受疾病严重程度的驱使，这种明确的HLA相关性已经出现在艾滋病中，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检测方法进行基于HLA的疾病风险分析的时代。我们认为，艾滋病病毒-艾滋病将被视为许多此类疾病中的第一种，其中遗传性HLA变异可以帮助预测疾病风险的终身变化。在SBIR中开发的技术将有助于提供那些新发现的HLA-AIDS相关性，作为一种低成本，基于人群的遗传测试。然而，也许更重要的是，我们将开发的技术平台（复杂的遗传测试+干燥状态样本收集）将被历史地视为未来几十年人口规模遗传学用于所有疾病的模式。毫无疑问，十年后，新技术将出现，比我们在这里开发的艾滋病芯片更好，更快，更便宜。然而，我们同样可以肯定的是，无论这些新的人口规模的遗传工具可能是什么，它们的使用方式，将非常像这个SBIR的“古特里卡+艾滋病芯片”配对。