Phase 1/2 of Taurine in Cystathionine Beta-Synthase Deficient Homocystinuria

描述（由申请人提供）： 胱硫醚β-合酶缺陷型同型胱氨酸尿症（CBSDH）是一种罕见的遗传性疾病，在出生时临床上无症状，但随着时间的推移具有显著的发病率和死亡率。随着新生儿筛查的扩大，这一点越来越被人们所认识。受影响的个体表现出增加的血液凝固、透镜问题、骨质疏松症、骨骼异常和智力残疾。虽然目前的治疗改善了结果，但存在局限性和不良副作用，并且治疗依从性差。因此，需要新的治疗策略。来自CBSDH基因工程小鼠模型的研究数据表明，氧化应激和全身性慢性炎症在这种疾病的发病机制中起着关键的主要起始作用，补充牛磺酸可减轻这些影响并改善功能，包括凝血正常化、认知改善和骨矿物质密度改善。 在本申请中，研究者提出了一项短期、单次给药、探索性1/2期研究，以确定除了安全性和药代动力学数据外，哪些参数可能对牛磺酸治疗有反应。这项多中心、开放标签研究将纳入12例年龄在8至50岁之间的CBSDH患者，这些患者将接受牛磺酸75 mg/kg（最多5 g），每日两次，总剂量为150 mg/kg/天（最多10 g/天），持续41/2天。仅出于安全性原因，前2例患者将接受25 mg/kg/剂（最大1.5 g）每日2次治疗。在审查安全性参数后，将剂量增加至计划剂量75 mg/kg/剂（最大5 g），每日两次。在研究期间，标准治疗将不会改变。患者将继续其现有的饮食限制治疗（如果存在）和甜菜碱治疗以及任何其他处方治疗。 在提案的具体目标1中，研究者将进行一项I期研究，旨在记录牛磺酸治疗的安全性和药代动力学特征，特别是在CBSDH患者中。在具体目标2中，研究者将进行II期研究，以研究在存在和不存在牛磺酸治疗的情况下CBSDH中氧化应激和炎症的血浆水平。根据初步研究的结果，通过测量硫代巴比妥酸反应物质（TBARS）和肿瘤坏死因子α（TNF-α）的血浆水平来评估氧化应激和炎症。 在具体目标3中，研究者将进行一项探索性系统研究，旨在确定CBSDH中氧化应激和炎症的其他标志物，以评估牛磺酸的治疗效果。 此外，他们将通过研究血浆甲硫氨酸循环代谢物、血小板聚集、内皮功能障碍和骨密度来研究这些生物标志物与发病机制的相关性。

DESCRIPTION (provided by applicant): Cystathionine beta-synthase deficient homocystinuria (CBSDH) is a rare inherited disorder that is clinically silent at birth but with significant morbidity and mortality over time. It is increasngly recognized since the introduction of expanded newborn screening. Affected individuals exhibit increased blood clotting, lens problems, osteoporosis, skeletal abnormalities, and intellectual disability. Although current treatments improve outcome, limitations and adverse side effects exist, and treatment compliance is poor. Consequently, a need for novel therapeutic strategies exists. Data from research on a genetically engineered mouse model of CBSDH indicates that oxidative stress and systemic chronic inflammation play a critical primary initiating role in the pathogenesis of this disorder and that supplementation with taurine mitigates these effects and improves function including normalization of coagulation, improved cognition, and improved bone mineral density. In this application, the investigators propose a short-term, single dose, exploratory Phase 1/2 study to identify which parameters are likely to respond to taurine treatment, in addition to safet and pharmacokinetic data. This multi-center, open label study will include 12 patients between ages 8 to 50 years old with CBSDH who will be given taurine 75 mg/kg (maximum 5 grams) twice a day for a total dose of 150 mg/kg/day (maximum 10 grams per day) for 41/2 days. For safety reasons only, the first two patients will be treated with a dose of 25 mg/kg/dose (maximum 1.5 g) twice daily. After review of safety parameters, the dose will then be increased to the planned dose of 75 mg/kg/dose (maximum 5 g) twice daily. During the study, the standard treatment will not be altered. Patients will continue their existing treatment of dietary restrictin, if present, and betaine therapy, and any other prescribed therapies. In specific aim 1 of the proposal, the investigators will perform a Phase 1 study designed to document the safety and pharmacokinetic characteristics of taurine treatment specifically in CBSDH patients. In specific aim 2, the investigators will perform a Phase 2 study to investigate the plasma levels of oxidative stress and inflammation in CBSDH in the presence and absence of taurine treatment. Oxidative stress and inflammation will be assessed by measurement of plasma levels of thiobarbituric acid reactive substances (TBARS) and tumor necrosis factor alpha (TNF-alpha), chosen based on the results of a preliminary study. In specific aim 3, the investigators will conduct an exploratory systematic study designed to identify additional markers of oxidative stress and inflammation in CBSDH with a view towards assessing the therapeutic effects of taurine. Additionally, they will investigate the relevance of these biomarkers to pathogenesis by studies of plasma methionine cycle metabolites, platelet aggregation, endothelial dysfunction, and bone mineral density.