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.
Cystathionine ?-synthase homocystinuria is a rare orphan disease that causes increased blood clotting, lens problems, osteoporosis, skeletal abnormalities, and intellectual disability. Its current treatment with a severe restricted diet in addition to treatment with betaine is often too cumbersome for patients to comply with and does not address all symptoms. In this human study, we will examine new pathophysiologic mechanisms, first identified in an animal model, and evaluate if additional treatment with taurine will correct these mechanisms and lead to improved health parameters.