Diagnosis & Biomarker Discovery Project

诊断

基本信息

批准号：
10480835
负责人：
Hudson H. Freeze
金额：
$ 40.8万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/10480835
关键词：
Address 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 Lead Link Lipids Measurement Measures Metabolic Diseases Monitor Mutation Natural History Oral Outcome Measure Patients Pattern Polysaccharides Population Process Proteins Serpins Serum Severities Severity of illness Staging Suggestion Systemic Therapy Techniques Technology Testing Transferrin Treatment Efficacy Urine Validation accurate diagnosis biomarker discovery biomarker identification 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

项目摘要

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/项目摘要先天性糖基化障碍（CDG）已迅速发展成为最大的代谢性疾病群之一疾病，但在没有自然病史、情感治疗和经过验证的生物标志物的情况下，对它们的描述很差与疾病严重程度相关并且没有全面的诊断工具。 PMM2-CDG 和先天性疾病半乳糖基化（例如 SLC35A2-CDG、PGM1-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疾病糖基化与 NGLY1 缺乏症的潜在非侵入性诊断生物标志物。一些久为人知的 CDG 类型，然而，像 ALG13-CDG 一样，仍然没有可靠、经过验证的诊断方法。我们的总体目标和总体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。我们将克服当前生化技术和生物标志物的缺点测量特定 CDG 的治疗效果和诊断。解决未满足的需求并实现我们的目标总体目标，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 PMM2-CDG； 2）开发定量生物标志物来诊断PGM1-CDG并监测半乳糖治疗效果； 3）开发定量生物标志物来诊断SLC35A2-CDG并监测半乳糖治疗效果； 4）验证用于诊断和跟踪 NGLY1 缺陷并监测 N-乙酰氨基葡萄糖 (GlcNAc) 治疗反应的生物标志物； 5) 验证 ALG13-CDG 的新型诊断生物标志物； 6) 使新患者符合一般 CDG 的资格并接纳其人口。这一目标对 CDG 社区的影响是双重的。我们将显着改善诊断 CDG 患者，通过改进诊断和生物标志物识别，我们将增加临床试验准备状态。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）以及他们通过可量化的生化检测对治疗（项目 3）的反应。相同的平行测量不同实验室的生物材料不仅会提高可靠性，而且将成为验证过程不可或缺的一部分并促进开发诊断疾病的标准生化测试的过程。这样的改进诊断对于评估疾病严重程度和验证生化结果测量非常重要或生物标志物，我们的努力将支持 CDG 即将进行的临床试验。使用最新状态的多种方法艺术技术将提供数据来评估该项目的整体成功。此外，生化验证可以提供评估其他新出现或尚未确定的糖基化疾病的框架。