Clinical Trials Project

临床试验项目-AbstrCAT/PROPOJET 摘要 饮食干预是治疗经典先天性缺陷的一种成功方法，旨在恢复 患者代谢物的正常水平。过去，单糖 D-半乳糖的积极作用已 已在高尔基相关 CDG 中记录。我们在 PGM1-CDG 和 SLC35A2-CDG 中的初步数据表明 补充 D-半乳糖可改善患者的聚糖合成，同时改善 临床症状。在另一种糖基化疾病 NGLY1 缺乏症中，临床前研究提供了不同的结果 该疾病的治疗目标。尽管有这些令人鼓舞的初步观察结果，我们确实需要临床 试验旨在 1) 评估口服 D-半乳糖补充剂对患有以下疾病的患者的长期治疗、剂量和安全性 PGM1-CDG； 2) 研究口服 D-半乳糖补充剂对患有另一种蛋白质的患者的功效 半乳糖基化缺陷 (SLC35A2-CDG) 和 3) 评估是否在 NGLY1 中补充口服 GlcNAc 缺陷可转化为人类疾病。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”来恢复 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-半乳糖补充剂在 SLC35A2-CDG（一种 低半乳糖基化疾病，使用癫痫发作控制、定量糖组学和经过验证的临床严重程度 评分（NPCRS）作为盲法交叉研究设计的终点； 2) 评估最佳剂量和长期剂量 使用经过验证的临床严重程度评分 (TPCRS) 和定量分析 D-半乳糖在 PGM1-CDG 中的安全性 糖组学作为开放标签剂量递增研究设计的终点，并且 3) 评估其安全性和效果 NGLY1 缺乏症患者口服 GlcNAc 补充剂可控制新型尿液生物标志物，控制癫痫发作 和泪液分泌作为终点。拟议的临床试验将填补即将进行的临床设计中的空白 CDG 和 NGLY1 试验，建立初始治疗方案并明确安全剂量 单糖疗法。这项研究的成果得到了自然历史研究和 诊断和生物标志物项目将提高大规模 2 期和 3 期临床试验的准备情况 通过验证临床进展评分和患者报告的结果（目标达成量表）进行临床试验 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.