Diagnosis & Biomarker Discovery Project

诊断

• 批准号: 10686334
• 负责人: Hudson H. Freeze
• 金额: $ 57.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686334
• 关键词: Address; Admission activity; Affect; Affective; Age; Biochemical; Biocompatible Materials; Biological Assay; Biological Markers; Cells; Cellular Assay; Clinical; Clinical Trials; Communities; Complex; Congenital Disorders; Congenital disorders of glycosylation; Data; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Disease Progression; Extrahepatic; Future; Galactose; Genetic Diseases; Immunoglobulins; Laboratories; Link; Lipids; Measurement; Measures; Metabolic Diseases; Monitor; Mutation; Natural History; Oral; Outcome Measure; Patients; Pattern; Polysaccharides; Population; Process; Proteins; Qualifying; Serpins; Serum; Severities; Severity of illness; Staging; Systemic Therapy; Techniques; Technology; Testing; Transferrin; Treatment Efficacy; Urine; Validation; accurate diagnosis; biomarker discovery; biomarker identification; biomarker validation; body system; clinical trial readiness; diagnostic biomarker; diagnostic tool; frontier; glycosylation; improved; mannosyl(5)-N-acetyl(2)-glucose; mannosyl(9)-N-acetylglucosamine2; molecular phenotype; noninvasive diagnosis; novel diagnostics; potential biomarker; profiles in patients; success; therapeutic biomarker; treatment response

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.

诊断和生物标志物发现-摘要/项目总结 先天性糖基化障碍（CDG）已迅速发展成为最大的代谢性疾病之一， 疾病，但在没有自然病史、情感治疗和经验证的生物标志物的情况下，它们的描述很差 与疾病严重程度相关，而没有全面的诊断工具。PMM 2-CDG与先天性疾病 半乳糖基化（如SLC 35 A2-CDG，PGM 1-CDG）是最常见的N-糖基化疾病， 新兴的潜在疗法。先天性去糖基化障碍是最近发现的一组异常糖基化的疾病。 糖基化与NGLY 1缺乏症的潜在非侵入性诊断生物标志物。一些长期已知的CDG类型， 然而，像ALG 13-CDG一样，仍然没有可靠的、经验证的诊断方法。我们的总体目标和 我们的目标是开发和验证新的生化诊断技术和治疗生物标志物， 未来的CDG临床试验我们将克服目前生物化学技术和生物标志物的缺点， 测量治疗效果和特异性CDG的诊断。为了满足未满足的需求， 总体目标，我们将1）开发和验证生物标志物，以监测临床试验中的治疗效果， PMM 2-CDG; 2）开发定量生物标志物以诊断PGM 1-CDG并监测半乳糖治疗功效; 3)开发定量生物标志物以诊断SLC 35 A2-CDG并监测半乳糖治疗疗效; 4）验证 生物标志物，用于诊断和跟踪NGLY 1缺乏症并监测N-乙酰葡糖胺（GlcNAc）治疗反应; 5)验证ALG 13-CDG的新诊断生物标志物; 6）使新患者合格并接受普通CDG 人口这一目标对社区发展小组的影响是双重的。我们将大大改善诊断， CDG患者，通过改进诊断和生物标志物的鉴定，我们将增加临床试验 准备就绪。实现这些目标应该使我们能够将疾病进展和疾病严重程度联系起来（项目1） 和他们对治疗的反应（项目3）与可量化的生化测定。相同的平行测量 在不同的实验室使用生物材料不仅会增加可靠性，而且会成为验证过程的组成部分 并有助于开发用于诊断疾病的标准生化测试的过程。这种改进的 诊断对于评估疾病的严重程度和通过验证生化结果测量将是重要的 我们的努力将支持即将进行的CDG临床试验。使用国家的多种方法- art technologies将提供数据，以评估该项目的总体成功情况。此外，生化验证 可以提供一个框架，用于评估其他新兴的或尚未确定的糖基化障碍。