Frontiers in Congenital Disorders of Glycosylation

先天性糖基化疾病的前沿

• 批准号: 10480825
• 负责人: Eva Morava-Kozicz
• 金额: $ 155.56万
• 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/10480825
• 关键词: Address; Affect; Age; Biochemical; Biological Assay; Biological Markers; Biology; Caring; Clinical; Clinical Research; Clinical Sciences; Clinical Trials; Complex; Congenital disorders of glycosylation; Data; Data Collection; Defect; Diagnosis; Diagnostic; Diagnostic Procedure; Dietary Intervention; Disease; Family health status; Fingerprint; Galactose; Glycoproteins; Health; Health Professional; Inborn Errors of Metabolism; Incidence; Knowledge; Laboratories; Life Expectancy; Link; Natural History; Oral; Organ; Outcome Measure; Patient Care; Patient Outcomes Assessments; Patient-Focused Outcomes; Patients; Physicians; Proteins; Quality of life; Rare Diseases; Research Personnel; Scientist; Screening procedure; Supplementation; Symptoms; Techniques; Testing; Therapeutic; United States National Institutes of Health; Variant; base; clinical practice; clinical trial readiness; diagnostic tool; dietary; disease natural history; exome sequencing; follow-up; frontier; glycosylation; improved; individualized medicine; novel; novel marker; patient registry; pilot trial; prospective; response; screening; success; symposium; therapeutic biomarker; therapy development; treatment research; variant of unknown significance; virtual

OVERALL-PROJECT SUMMARY/ABSTRACT Genetically defined in the 1990s, congenital disorders of glycosylation (CDG) consist of 130+ different inborn metabolism errors with overall incidence of ~>1:100,000. Thirty years later: there is no disease natural history data, no comprehensive patient registry, and no reliable screening for many CDG types. Furthermore, almost no therapy is available. We do have a strong patient association, committed clinicians, and a growing scientist group forming a virtual consortium, which closely collaborates to improve patient outcomes. We need prospective natural history data on health concerns to impact quality of life, validate disease biomarkers, and develop reliable diagnostics to increase clinical trial readiness. Our preliminary findings include retrospective natural history data, as well as data on novel biochemical biomarkers and techniques containing glycomics, which were established and validated in pilot trials for screening and diagnostics in CDG. The first clinical trials in specific CDG types started with dietary intervention, as is the most common approach in CDG therapy. Our collaborating group pioneered in these trials, most importantly in D- galactose therapy in PGM1-CDG. We also initiated the first (limited) PMM2-CDG natural history study, in parallel with the NIH single center CDG natural history study. Our nation-wide network of regional centers will further collaborate on diagnosis, follow up, treatment and clinical research in CDG. Our overreaching aims are a) establishing early reliable diagnosis b) increase diagnostic success and sensitivity, c) improve our knowledge on the natural history, d) find new biomarkers and e) develop therapies in congenital disorders of glycosylation. We will include all types of CDGs, focusing on three major biochemical disorder groups within multifaceted CDG: a) the most common form of CDG; PMM2-CDG, b) the group of potentially treatable disorders affecting protein galactosylation, and c) a defect from the new glycosylation disorder group (disorders of de-glycosylation)--NGLY1 deficiency. To achieve these milestones, we will apply cross-disciplinary, team-based clinical research to 1) define natural history, validate patient reported outcome and share knowledge on congenital disorders of glycosylation; 2) develop and validate new biochemical diagnostic techniques and therapeutic biomarkers for clinical trials; and 3) restore appropriate glycosylation to improve clinical symptoms and quality of life in disorders of glycosylation. Partners in our consortium have collaborated for more than a decade in finding solutions to complex problems in CDG biology, sharing knowledge, individualizing therapy, organizing patient conferences, and supporting physicians caring for CDG patients. We have improved patient care in this rare disease, but it is not enough. Leveraging on a nation-wide network, this proposal's aims begin to relieve decades of unresolved questions, address lack of knowledge, develop treatment and meet currently unmet patient need.

总体-项目总结/摘要 在20世纪90年代的遗传学定义中，先天性糖基化疾病（CDG）由130多种不同的先天性糖基化疾病组成。 代谢异常，总发生率约>1：100，000。30年后：没有疾病自然史数据， 没有全面的患者登记，也没有对许多CDG类型进行可靠的筛查。此外，几乎没有治疗 服务器租用-美国服务租用我们确实有一个强大的病人协会，致力于临床医生，和一个不断增长的科学家群体，形成了一个 虚拟联盟，密切合作，以改善病人的结果。我们需要前瞻性的自然历史 关于健康问题的数据，以影响生活质量，验证疾病生物标志物，并开发可靠的诊断方法， 增加临床试验准备。 我们的初步发现包括回顾性自然史数据，以及新的生物化学生物标志物的数据 和含有糖组学的技术，这些技术在筛选和 CDG诊断。第一批针对特定CDG类型的临床试验始于饮食干预， CDG治疗的常用方法。我们的合作小组在这些试验中处于领先地位，最重要的是在D- 半乳糖治疗PGM 1-CDG。我们还同时启动了第一个（有限的）PMM 2-CDG自然史研究， NIH单中心CDG自然史研究。我们的全国性区域中心网络将进一步 在CDG的诊断、随访、治疗和临床研究方面进行合作。 我们的目标是：a）建立早期可靠的诊断B）提高诊断的成功率和敏感性，c） 提高我们对自然史的认识，d）发现新的生物标志物，e）开发先天性心脏病的治疗方法。 糖基化障碍。我们将包括所有类型的CDG，重点是三个主要的生化紊乱组 在多方面CDG中：a）最常见的CDG形式; PMM 2-CDG，B）潜在可治疗的CDG组， 影响蛋白质半乳糖基化的病症，和c）来自新的糖基化病症组的缺陷（糖基化病症， 去糖基化）-NGLY 1缺陷。 为了实现这些里程碑，我们将应用跨学科，以团队为基础的临床研究，以1）定义自然 历史，验证患者报告的结果并分享关于先天性糖基化疾病的知识; 2） 为临床试验开发和验证新的生化诊断技术和治疗生物标志物;以及3） 恢复适当的糖基化，以改善糖基化障碍的临床症状和生活质量。 我们联盟中的合作伙伴已经合作了十多年，为复杂的问题寻找解决方案， CDG生物学，分享知识，个性化治疗，组织患者会议， 护理CDG患者的医生。我们已经改善了这种罕见疾病的患者护理，但这还不够。 利用一个全国性的网络，这项提案的目标开始是解决几十年来悬而未决的问题， 解决知识缺乏问题，开发治疗方法，满足目前未满足的患者需求。