Clinical Trials Project

临床试验项目--ABSTRCAT/PRPOJET总结 饮食干预一直是治疗经典先天错误的一种成功方法，旨在恢复 患者体内代谢物水平正常。在过去，单糖D-半乳糖的积极作用 已在高尔基相关CDG中记录。我们在PGM1-CDG和SLC35A2-CDG中的初步数据显示 补充D-半乳糖可改善患者的糖链合成 临床症状。在另一种糖基化障碍，NGLY1缺乏症中，临床前研究提供了不同的 这种疾病的治疗目标。尽管有这些令人鼓舞的初步观察，我们确实需要临床 1)评价口服D-半乳糖补充剂对慢性支气管炎患者的长期疗效、剂量和安全性 PGM1-CDG；2)研究口服D-半乳糖对另一种蛋白患者的疗效- 半乳糖化缺陷(SLC35A2-CDG)和3)评估口服GlcNAc是否对NGLY1 缺乏症可以转化为人类的疾病。我们的科学前提是使用膳食糖，D- 半乳糖和N-乙酰-氨基葡萄糖可通过影响“代谢产物通量”来恢复CDG的糖基化。 调节和促进糖基化途径改善CDG的临床症状和生活质量 病人。我们建议1)评估补充D-半乳糖对SLC35A2-CDG的疗效和安全性。 低半乳糖化紊乱，使用癫痫控制，定量血糖和证实的临床严重性 在盲法交叉研究设计中作为终点的评分(NPCRS)；2)评估最优剂量和长期 D-半乳糖在PGM1-CDG中的安全性研究 将糖类药物作为开放标签剂量递增研究设计的终点，以及3)评估 口服GlcNAc对NGLY1缺乏症患者一种新的尿液生物标志物癫痫控制的影响 和泪液分泌物，作为终点。拟议的临床试验将填补即将到来的临床试验的设计空白。 通过建立初始治疗方案和明确CDG和NGLY1的安全剂量进行CDG和NGLY1的试验 单糖疗法。这项研究的成果，由自然历史研究和 诊断和生物标记物项目将增加大规模第二阶段和第三阶段的临床试验准备 通过验证临床进展分数和患者报告的结果进行临床试验(目标实现度量表) 以及先进的诊断和生物标志物的发现。

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.