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

描述(由申请人提供)： 胱硫醚β-合酶缺陷型同型半胱氨酸尿症(CBSDH)是一种罕见的遗传性疾病，出生时临床上无症状，但随着时间的推移有显著的发病率和死亡率。自从扩大新生儿筛查以来，这一点得到了越来越多的认可。受影响的个体表现出凝血增加、晶状体问题、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，但存在局限性和副作用，治疗依从性较差。因此，存在对新的治疗策略的需求。对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启动作用，补充牛磺酸可以缓解这些影响，并改善功能，包括凝血正常化、改善认知和改善骨密度。 在这一应用中，研究人员建议进行一项短期、单剂、探索性的1/2阶段研究，以确定除了SAFET和药代动力学数据外，哪些参数可能对牛磺酸治疗有反应。这项多中心的开放标签研究将包括12名年龄在8岁至50岁之间的CBSDH患者，他们将每天两次服用牛磺酸75毫克/公斤(最多5克)，总剂量为150毫克/公斤/天(每天最多10克)，为期41天半。仅为安全起见，头两名患者将接受每日两次的治疗，剂量为25毫克/公斤/剂量(最高1.5克)。在审查安全参数后，剂量将增加到计划剂量75毫克/公斤/剂量(最高5克)，每天两次。在研究期间，标准治疗不会改变。患者将继续他们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。 在该提案的具体目标1中，研究人员将进行一项旨在证明牛磺酸治疗CBSDH患者的安全性和药代动力学特征的第一阶段研究。在具体目标2中，研究人员将进行第二阶段研究，以调查牛磺酸治疗前后CBSDH患者的血浆氧化应激和炎症水平。氧化应激和炎症将通过测量血浆硫代巴比妥酸反应物质(TBARS)和肿瘤坏死因子α(TNF-α)的水平来评估，这两种物质是根据初步研究的结果选择的。在具体目标3中，研究人员将进行一项探索性的系统研究，旨在确定CBSDH中氧化应激和炎症的其他标记物，以期评估牛磺酸的治疗效果。此外，他们还将通过研究血浆蛋氨酸循环代谢产物、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.