Identification of a Multi-Analyte Profile for Primary Hyperoxaluria

描述（由申请人提供）：原发性高草酸尿症，1型（PH1）是一种罕见的单基因疾病，其中AGXT基因突变导致肝脏过量产生草酸，导致肾脏和其他器官广泛沉积草酸钙。不幸的是，PH1疾病的进展尚不清楚。尽管鉴定出AGTX突变，但在这些患者中几乎没有基因型-表型相关性，肾结石的形成和肾功能丧失似乎以偶然的方式进行。许多患者可能发展为终末期肾病（ESKD），尽管目前的支持治疗。准确检测PH1并识别快速发展为ESKD的高风险个体的客观诊断是尚未满足的临床需求。显然，没有单一的分子标记，或一小群标记，将能够满足这一需求。常见的蛋白质组学技术，如酶联免疫吸附测定（ELISA），缺乏同时定量多种生物标志物的能力。对每一种假定的生物标志物进行一次评估需要花费大量的时间、成本和样本量。新技术缺乏灵敏度、精度和自动化。因此，系统地识别蛋白质谱、预测临床事件风险、评估治疗反应和确定潜在机制的能力受到严重限制。基于规则的医学（RBM）通过开发基于头部的多路免疫测定来识别疾病特异性的多分析物谱（MAPs），解决了这些限制。令人兴奋的初步数据表明，MAP技术非常适合于并行筛选大量标记物，以确定与PH1相关的蛋白质谱，并可能提供对疾病病程的深入了解。在第一阶段，RBM和儿童纪念医院（CMH）建议利用这种定量蛋白质组学方法来比较从诊断为PH1的患者与年龄和性别匹配的对照人群中获得的尿液样本中的蛋白质谱。201个蛋白的表达水平和表达模式将被研究。我们希望从这项研究中获得的生理学见解可以用来更好地定义与PH1相关的病理机制。在第二阶段，将对第一阶段工作中为PH1确定的MAP进行前瞻性验证。将确定每种分析物的敏感性、特异性、阳性和阴性预测值，以及用于预测疾病进展为ESKD的生物标志物的MAP。此外，将根据正常人群和PH1人群的年龄和性别，制定儿童和青少年MAP分析的拟议生理范围。这种范围值通常用于诊断和干预，可作为未来研究的参考，并可用于诊断测试和治疗算法的开发。PH1患者和ESKD高风险患者的新生物标志物模式的鉴定，将通过客观选择治疗疗程或剂量、确定治疗效果，并为开发和评估新治疗提供框架，从而改善病情的管理。

DESCRIPTION (provided by applicant): Primary hyperoxaluria, type 1 (PH1) is a rare, monogenic disorder in which a mutation in the AGXT gene leads to overproduction of oxalate by the liver, resulting in widespread deposition of calcium oxalate in the kidneys and other organs. Unfortunately, PH1 disease progression is not understood. Despite identification of the AGTX mutation, there is little genotype-phenotype correlation in these patients, with kidney stone formation and loss of kidney function proceeding in a seemingly haphazard fashion. Many patients may progress to end- stage kidney disease (ESKD), despite current supportive therapy. An objective diagnostic that accurately detects PH1 and identifies individuals at high risk for rapid progression to ESKD is an unmet clinical need. Clearly, no single molecular marker, or small group of markers, will be able to meet this need. Common proteomic technologies, such as Enzyme-Linked Immunosorbent Assay (ELISA), lack the ability to quantify multiple biomarkers simultaneously. One-at-a-time assessment of each putative biomarker incurs considerable time, cost and sample volume. Newer technologies lack sensitivity, precision and automation. The ability to systematically identify protein profiles, predict risk of clinical events, evaluate therapeutic response, and define underlying mechanisms is thereby limited severely. Rules-Based Medicine (RBM) resolved these limitations by developing bead-based, multiplexed immunoassays for identifying disease-specific Multi-Analyte Profiles (MAPs). Exciting preliminary data indicates that MAP technology is well suited for screening large numbers of markers in parallel to identify protein profiles associated with PH1, and may provide insight into the disease course. During Phase I, RBM, and Children's Memorial Hospital (CMH) propose to utilize this quantitative proteomics approach to compare the protein profiles in urine samples obtained from patients diagnosed with PH1 vs. age- and gender-matched control populations. The level and pattern of expression for 201 proteins will be studied. It is expected that the physiological insight obtained from the proposed study may be used to better define the pathological mechanisms associated with PH1. During Phase II, a prospective validation of the MAP identified for PH1 during Phase I efforts will be performed. The sensitivity, specificity,and positive and negative predictive values for each analyte, as well as, the MAP of biomarkers for predicting progression of the disease to ESKD will be determined. In addition, a proposed physiological range of MAP analytes for children and adolescents will be developed based on age, and gender for both the normal and PH1 populations. Such range values, typically used for diagnosis and intervention, can be used as a reference for future studies and for the development of both a diagnostic test and therapeutic algorithms. The identification of novel biomarker patterns of individuals with PH1, as well as, individuals at high risk for rapid progression to ESKD, will allow for improved management of the condition by objective selection of treatment course or dosage, determining treatment effectiveness, and providing a framework for developing and evaluating new treatments.