Clinical Trials Project

临床试验项目-ABSTRCAT/PRPOJET总结 饮食干预已成为治疗典型先天性缺陷的成功方法，旨在恢复 患者体内代谢物的正常水平。在过去，单糖的积极作用，D-半乳糖有 在高尔基体相关的CDG中有记载。我们在PGM 1-CDG和SLC 35 A2-CDG中的初步数据显示， 补充D-半乳糖的患者导致聚糖合成的改善， 临床症状。在另一种糖基化疾病NGLY 1缺乏症中，临床前研究提供了不同的 疾病的治疗目标。尽管这些令人鼓舞的初步观察，我们确实需要临床 试验1）评价口服D-半乳糖补充剂在患有以下疾病的患者中的长期治疗、剂量和安全性： PGM 1-CDG; 2）研究口服D-半乳糖补充剂在另一种蛋白质- 半乳糖基化缺陷（SLC 35 A2-CDG）和3）评估NGLY 1中口服GlcNAc补充是否 缺乏症可以转化为人类疾病。我们的科学前提是，使用膳食糖，D- 半乳糖和N-乙酰氨基葡萄糖将通过影响“代谢物通量”恢复CDG中的糖基化， 调节和促进糖基化途径，从而改善CDG的临床症状和生活质量 患者我们建议：1）评估D-半乳糖补充在SLC 35 A2-CDG中的有效性和安全性， 低半乳糖基化障碍，使用癫痫控制、定量糖组学和经验证的临床严重程度 评分（NPCRS）作为盲法交叉研究设计中的终点; 2）评估最佳剂量和长期 使用经验证的临床严重程度评分（TPCRS）和定量分析， 糖组学作为开放标签剂量递增研究设计中的终点，和3）评价 口服GlcNAc补充剂对NGLY 1缺乏患者的一种新的尿生物标志物--癫痫控制的影响 和泪液分泌作为终点。拟议的临床试验将填补即将到来的临床试验设计的空白。 通过建立初始治疗方案和阐明CDG和NGLY 1的安全剂量， 单糖疗法。从这项研究中得出的结论，得到了自然历史研究和 诊断和生物标志物项目将增加大规模2期和3期临床试验的准备 通过验证临床进展评分和患者报告的结局（目标达成量表）进行的临床试验 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.