Frontiers in Congenital Disorders of Glycosylation

先天性糖基化疾病的前沿

• 批准号: 10017346
• 负责人: Eva Morava-Kozicz
• 金额: $ 170.46万
• 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/10017346
• 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; Diet; 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; Readiness; Research Personnel; Scientist; Screening procedure; Supplementation; Symptoms; Techniques; Testing; Therapeutic; United States National Institutes of Health; Variant; base; clinical practice; 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; tool; 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.

总体项目摘要/摘要 在1990年代的遗传学定义，糖基化的先天性疾病（CDG）由130多种不同的先天性组成 代谢错误，总体发生率为〜> 1：100,000。 30年后：没有疾病自然史数据， 没有全面的患者注册表，也没有对许多CDG类型的可靠筛查。此外，几乎没有治疗 可用。我们确实有牢固的患者联系，致力于临床医生以及成长的科学家组，形成了 虚拟财团，该财团紧密合作以改善患者的结果。我们需要潜在的自然历史 有关影响生活质量，验证疾病生物标志物并开发可靠诊断的数据的数据 增加临床试验准备。 我们的初步发现包括回顾性自然历史数据以及有关新型生化生物标志物的数据 和含有糖基质的技术，这些技术是在试验试验中建立和验证的，以进行筛查和 CDG中的诊断。特定CDG类型的第一次临床试验始于饮食干预，这是最多的 CDG治疗中的常见方法。我们的合作小组在这些试验中开创了先驱，最重要的是在D-中 PGM1-CDG中的半乳糖治疗。我们还启动了第一个（有限的）PMM2-CDG自然历史研究，并行 NIH单中心CDG自然史研究。我们在全国范围的地区中心网络将进一步 在CDG中进行诊断，随访，治疗和临床研究的合作。 我们的推广目标是a）建立早期可靠的诊断b）提高诊断成功和敏感性，c） 提高我们对自然史的知识，d）找到新的生物标志物并E）开发先天性的疗法 糖基化的疾病。我们将包括所有类型的CDG，重点关注三个主要的生化疾病组 在多方面的CDG中：a）CDG最常见的形式； PMM2-CDG，b）可能可治疗的组 影响蛋白质半乳糖基化的疾病，c）新糖基化障碍群的缺陷（疾病的疾病 去糖基化）-NGLY1缺陷。 为了实现这些里程碑，我们将将基于团队的跨学科，基于团队的临床研究应用于1）定义自然 病史，验证患者报告了结果并分享有关糖基化先天性疾病的知识； 2） 开发和验证新的生化诊断技术和用于临床试验的治疗生物标志物； 3） 恢复适当的糖基化，以改善糖基化疾病的临床症状和生活质量。 我们财团的合作伙伴合作了十多年，以寻找解决复杂问题的解决方案 CDG生物学，共享知识，个性化治疗，组织患者会议和支持 照顾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。 在利用全国性网络上，该提案的目标开始缓解数十年来未解决的问题， 解决缺乏知识，发展治疗并满足目前未满足的患者需求。