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

胱硫醚β合酶缺陷性同型半胱氨酸尿症(CBSDH)是一种遗传性疾病 出生时临床上无症状，但随着时间的推移，即使在最好的情况下也会有显著的发病率和死亡率 治疗性干预。目前对这种情况的治疗是次优的，部分原因是问题 在过去的40多年里，这种情况一直没有显著改善。来自一项研究的数据 CBSDH基因工程小鼠模型表明氧化应激和系统性 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 牛磺酸的治疗显著减轻了这些影响。这项研究翻译了这一基本 实验室研究进入正式的人类临床研究，并调查一种 有希望的新的治疗干预措施。 牛磺酸补充剂已被应用于其他疾病，但没有任何副作用。 但它还没有在CBSDH进行正式评估。目前缺乏药物动力学研究。 因此，在我们建议的具体目标1中，我们将进行阶段1研究 旨在记录牛磺酸治疗的安全性和药代动力学特征 尤其是在CBSDH患者中。这项研究将包括牛磺酸水平的药代动力学分析 以求出Cmax、T1/2和AUC，并生成牛磺酸在CBSDH中给药的安全性数据 病人。 对CBSDH患者和小鼠血浆样本的初步分析表明， CBSDH导致慢性氧化应激和炎症状态。建议的研究目的是 在正式的对照人体试验中确认这一发现，并评估原则证据 牛磺酸可以减轻这种氧化应激和炎症。因此，在具体目标2中，我们 将进行2a期研究，以调查血浆氧化应激水平和 牛磺酸治疗前后CBSDH的炎症反应。氧化应激和 将通过测定血浆中硫代巴比妥酸反应性水平来评估炎症。 物质(TBARS)和肿瘤坏死因子(TNF-β)。这些标记是根据结果选择的 初步研究的结果。 高凝状态和骨密度降低是人CBSDH的主要特征。 先前的工作表明，牛磺酸在CBSDH小鼠模型中使这些特征正常化。在……里面 具体目标3，我们将进行探索性的系统研究，旨在确定其他 CBSDH中氧化应激和炎症的标记物 牛磺酸的治疗作用。此外，我们还将调查这些生物标志物的相关性。 通过对血小板聚集、内皮功能障碍和骨矿物质的研究来探讨其发病机制 密度。这些拟议研究的完成将增加我们对 CBSDH的发病机制，并为未来的2b期研究提供候选标记。

Cystathionine beta-synthase deficient homocystinuria (CBSDH) is an inherited disorder that is clinically silent at birth but with significant morbidity and mortality over time even with the best therapeutic intervention. Current treatment for this condition is sub-optimal due in part to issues of compliance and has not improved significantly for over 40 years. 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 treatment with taurine significantly mitigates these effects. This study translates this basic laboratory research into formal human clinical studies, and investigates the efficacy of a promising new therapeutic intervention. Taurine supplementation has been applied to other diseases without any adverse side effects but it has not been formally assessed in CBSDH. Currently there is a paucity of pharmacokinetic data for taurine Thus, in specific aim 1 of our proposal, we will perform a phase 1 study designed to document safety and pharmacokinetic characteristics of taurine treatment specifically in CBSDH patients. This study will include pharmacokinetic analysis of taurine levels to derive Cmax, T1/2, and AUC, and generate safety data on taurine administration in CBSDH patients. Preliminary analysis of plasma samples from CBSDH patients and mice has indicated that CBSDH induces a state of chronic oxidative stress and inflammation. The proposed study aims to confirm this finding in a formal controlled human trial, and to assess the proof of principle that taurine mitigates this oxidative stress and inflammation. Consequently, in specific Aim 2, we will perform a Phase 2a 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 determination of plasma levels of thiobarbituric acid reactive substances (TBARS) and TNF-¿ respectively. These markers were chosen based on the results of a preliminary study. Hypercoagulability and decreased bone mineral density are key features of human CBSDH. Previous work indicates that taurine normalizes these features in a mouse model of CBSDH. In specific aim 3, we 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, we will investigate the relevance of these biomarkers to pathogenesis by studies of platelet aggregation, endothelial dysfunction, and bone mineral density. Completion of these proposed studies will both increase our knowledge of pathogenesis in CBSDH and deliver candidate markers for a future phase 2b study.