Diagnosis & Biomarker Discovery Project

诊断和生物标记物发现-摘要/项目摘要 先天性糖基化异常(CDG)已迅速发展成为最大的代谢性疾病之一 疾病，然而，如果没有自然病史、情感治疗和有效的生物标志物，对它们的描述很差 与疾病严重程度相关，没有全面的诊断工具。PMM2-CDG与先天性疾病 半乳糖化(如SLC35A2-CDG、PGM1-CDG)是最常见的N-糖基化紊乱， 新兴的潜在疗法。先天性去糖基化障碍是新近发现的一组异常 NGLY1缺乏症中潜在的非侵入性诊断生物标志物的糖基化作用。一些久负盛名的CDG类型， 然而，像ALG13-CDG一样，仍然没有可靠的、经过验证的诊断方法。我们的总体目标和 超越的目标是开发和验证新的生化诊断技术和治疗性生物标记物 未来的CDG临床试验。我们将克服目前生化技术和生物标记物的缺点 检测特异性CDG的疗效和诊断学。要解决未得到满足的需求并完成我们的 总体目标，我们将1)开发和验证生物标志物，以在临床试验中监测治疗效果 PMM2-CDG；2)开发诊断PGM1-CDG和监测半乳糖治疗效果的定量生物标志物； 3)开发诊断SLC35A2-CDG和监测半乳糖治疗疗效的定量生物标志物；4)验证 诊断和跟踪NGLY1缺乏症和监测N-乙酰氨基葡萄糖(GlcNAc)治疗反应的生物标志物； 5)验证ALG13-CDG的新诊断生物标记物；6)符合并接纳新的患者进入普通CDG 人口。这一目标对CDG社区的影响是双重的。我们将显著提高对 CDG患者，通过改进诊断和识别生物标记物，我们将增加临床试验 准备好了。实现这些目标应使我们能够将疾病进展和疾病严重程度联系起来(项目1) 以及他们对治疗的反应(项目3)，采用可量化的生化分析。相同的平行测量 不同实验室的生物材料不仅将增加可靠性，而且将是验证过程的组成部分 并促进制定诊断疾病的标准生化测试的进程。这样的改进 诊断对于评估疾病的严重程度以及通过验证生化结果测量将是重要的 或生物标记物，我们的努力将支持CDG即将进行的临床试验。使用国情咨文的多种方法 ART技术将提供数据来评估该项目的整体成功。此外，生化验证 可为评估其他新出现的或尚未确定的糖基化紊乱提供一个框架。

DIAGNOSTICS AND BIOMARKER DISCOVERY-ABSTRACT/PROJECT SUMMARY Congenital disorders of glycosylation (CDG) have rapidly developed into one of the largest group of metabolic disorders, yet they are poorly described without natural histories, affective treatment, validated biomarkers correlating with disease severity and without comprehensive diagnostic tools. PMM2-CDG and congenital disorders of galactosylation (e.g. SLC35A2-CDG, PGM1-CDG) are the most common N-glycosylation disorders with emerging potential therapies. Congenital disorders of de-glycosylation is a recently discovered group of abnormal glycosylation with a potential noninvasive diagnostic biomarker in NGLY1 deficiency. Some long-known CDG types, like ALG13-CDG however still have no reliable, validated diagnostic methods. Our overall objective and overreaching aim is to develop and validate new biochemical diagnostic techniques and therapeutic biomarkers for future CDG clinical trials. We will overcome the shortcomings of current biochemical techniques and biomarkers in measuring therapeutic efficacy and diagnostics of specific CDG. To address the unmet need and accomplish our overall objective, we will 1) develop and validate biomarkers to monitor therapeutic efficacy in clinical trials for PMM2-CDG; 2) develop quantitative biomarkers to diagnose PGM1-CDG and monitor galactose therapy efficacy; 3) develop quantitative biomarkers to diagnose SLC35A2-CDG and monitor galactose therapy efficacy; 4) validate biomarker to diagnose and follow NGLY1 deficiency and monitor N-acetylglucosamine (GlcNAc) therapy response; 5) validate novel diagnostic biomarkers for ALG13-CDG; 6) qualify and admit new patients to the general CDG population. The impact of this aim on the CDG community is twofold. We will significantly improve diagnostics of patients with CDG, and through improved diagnostics and identification of biomarkers we will increase clinical trial readiness. Achieving these aims should enable us to correlate disease progression and disease severity (Project 1) and their response to therapy (Project 3) with quantifiable biochemical assays. Parallel measurements of the same biomaterial at the different laboratories will not only increase reliability, but will be integral to the validation process and facilitate the process of developing standard biochemical test for diagnosis of the disorders. Such improved diagnostics will be important to assess disease severity and through validation of biochemical outcome measures or biomarkers our efforts will support upcoming clinical trials in CDG. The multiple approaches using state-of-the- art technologies will provide data to assess the overall success of the project. Moreover, the biochemical validations may provide a framework for assessing other emerging or yet-to-be identified glycosylation disorders.