Clinical Trials Project

临床试验项目

• 批准号: 10264860
• 负责人: Eva Morava-Kozicz
• 金额: $ 25.99万
• 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/10264860
• 关键词: Address; Animal Model; Antithrombins; Biochemical Genetics; Biological; Biological Assay; Biological Markers; Blinded; Bypass; Clinical; Clinical Trials; Congenital disorders of glycosylation; Cross-Over Studies; Data; Defect; Diagnostic; Dietary Intervention; Dietary Sugars; Disease; Dose; Galactitol; Galactose; Glucosamine; Goals; Golgi Apparatus; Hereditary Disease; Human; Liver; Mannose; Metabolic; Metabolic Pathway; Monosaccharides; Natural History; Oral; Pathway interactions; Patient Outcomes Assessments; Patients; Phase II Clinical Trials; Phase III Clinical Trials; Polysaccharides; Proteins; Public Health; Quality of life; Research Design; Safety; Seizures; Severities; Supplementation; Symptoms; Treatment Protocols; Ultrasonography; Up-Regulation; Urine; biomarker discovery; clinical trial readiness; design; dosage; efficacy evaluation; efficacy study; frontier; galactose-1-phosphate; glycosylation; improved; insight; novel; open label; preclinical study; primary endpoint; secondary endpoint; sugar; therapeutic target; urinary

CLINICAL TRIAL PROJECT-ABSTRCAT/PRPOJET SUMMARY Dietary intervention has been a successful approach of treatment in classic inborn errors, aiming at restoring normal levels of metabolites in patients. In the past, a positive effect of the monosaccharide, D-galactose has been documented in Golgi related CDG. Our preliminary data in PGM1-CDG and SLC35A2-CDG showed that supplementation of patients with D-galactose leads to improvement of glycan synthesis parallel with improving clinical symptoms. In another glycosylation disorder, NGLY1 deficiency, preclinical studies offered a different therapeutic target for the disease. Despite these encouraging preliminary observations we do need clinical trials to 1) evaluate long-term therapy, dosage and safety of oral D-galactose supplementation in patients with PGM1-CDG; 2) study the efficacy of oral D-galactose supplementation in patients with another protein- galactosylation defect (SLC35A2-CDG) and 3) evaluate whether oral GlcNAc supplementation in NGLY1 deficiency is translatable to the human disorder. Our scientific premise is that the use dietary sugars, D- galactose and N-Acetyl-Glucosamine will restore glycosylation in CDG by influencing “metabolite fluxes” to regulate and boost glycosylation pathways leading to improved clinical symptoms and quality of life of CDG patients. We propose to 1) evaluate efficacy and safety of D-galactose supplementation in SLC35A2-CDG, a disorder of hypogalactosylation, using seizure control, quantitative glycomics and validated clinical severity score (NPCRS) as endpoints in a blinded, cross-over study design; 2) assess optimal dosing and long-term safety of D-galactose in PGM1- CDG using validated clinical severity score (TPCRS) and quantitative glycomics as endpoints in an open label dose escalation study design and 3) evaluate the safety and effect of oral GlcNAc supplementation in patients with NGLY1 deficiency on a novel urinary biomarker, seizure control and tear secretion, as end points. The proposed clinical trials will fill gaps in the design of upcoming clinical trials in CDG and NGLY1 by establishing initial treatment regimens and clarifying safe dosage for monosaccharide therapies. Deliverables from this study, supported by the natural history study and the diagnostics and biomarker project will increase clinical trial readiness for large-scale Phase 2 and Phase 3 clinical trials by validating clinical progression scores and patient reported outcomes (Goal Attainment Scale) as well as advanced diagnostics and biomarker discoveries.

临床试验项目-ABSTRCAT/PRPOJET摘要 饮食干预一直是经典天生错误的成功治疗方法，旨在恢复 患者代谢物的正常水平。过去，单糖的积极作用，D-半乳糖具有 我们在与高尔基体相关的CDG中有记录。我们在PGM1-CDG和SLC35A2-CDG中的初步数据表明 补充D-半乳糖患者会导致与平行的聚糖合成改善与改善 临床症状。在另一种糖基化障碍中，NGLY1缺乏症，临床前研究提供了不同的 该疾病的治疗靶标。尽管这些令人鼓舞的初步观察，我们确实需要临床 1）评估患者的长期治疗，剂量和口服D-半乳糖的安全性 PGM1-CDG; 2）研究另一种蛋白质的患者口服D-半乳糖的效率 半乳糖基化缺陷（SLC35A2-CDG）和3）评估NGLY1中是否补充口服GlcNAC。 缺乏症可以翻译成人类混乱。我们的科学前提是使用饮食糖D- 半乳酮和N-乙酰基葡萄糖胺将通过有影响力的“代谢物通量”恢复CDG中的糖基化。 调节和增强糖基化途径，从而改善CDG的临床症状和生活质量 患者。我们提出1）评估Slc35a2-CDG中D-半乳糖补充的有效性和安全性 癫痫控制，定量体操和验证的临床严重程度 得分（NPCR）作为盲目的，交叉研究设计的终点； 2）评估最佳剂量和长期 使用经过验证的临床严重程度评分（TPCR）和定量的D-半乳糖在PGM1-CDG中的安全性 甘露科学作为开放标签剂量升级研究设计的终点，3）评估的安全性和效果 NGLY1缺乏症患者的口服GLCNAC补充新型尿生物标志物癫痫 和泪水分泌，作为终点。拟议的临床试验将填补即将到来的临床设计的空白 通过建立初始治疗方案并澄清安全剂量，在CDG和NGLY1中进行试验 单糖疗法。这项研究的可交付成果，在自然历史研究和 诊断和生物标志物项目将增加大规模2和3阶段的临床试验准备就绪 临床试验通过验证临床进展评分和患者报告的预后（目标达到量表）来进行临床试验 以及先进的诊断和生物标志物发现。