Oxidative Stress Markers In Inherited Homocystinuria And The Impact Of Taurine

Study Overview
=================
Brief Summary
-----------------
Cystathionine beta-synthase deficiency is an inherited disease that results in elevation of a substance called homocysteine (Hcy) in blood and urine. Individuals with this disorder have a very high risk for developing blood clots and are at risk for developing eye and bone abnormalities. Current treatments are generally difficult to follow and can fail. Development of additional therapies has been limited by lack of understanding of how the disease works. The purpose of this study is to see if oxidative stress and inflammation are involved in the disease process and if short-term supplementation with taurine is an effective treatment. Funding source: FDA.

Detailed Description
-----------------
Cystathionine beta-synthase deficient homocystinuria(CBSDH) is an inherited disease that results in elevation of a substance called homocysteine(Hcy)in blood and urine. Individuals with this disorder have a very high risk for developing blood clots that can cause a stroke or other life-threatening problems. In addition, these individuals have bone and joint tissue abnormalities. Current treatment with an extremely strict diet and medication (betaine) is very difficult to follow, and often fails. Development of additional treatment strategies has been limited by a lack of knowledge and understanding of how this disease works. Hence, there is a need to better understand what causes the blood clots and the bone and joint tissue abnormalities. New data suggest that oxidative stress and inflammation play a central role in animals with this disease. Limited data on humans with this disease support this as well. Further, data from animals with this disease suggests that taurine, a natural body substance and food product, which is low in these patients, mitigates this effect. This study is designed to follow-up on these data. The purpose of the study is to increase our understanding of the disease process in this disorder, and to see in a pilot study if short-term supplementation with taurine is an effective intervention. The aims of the study are to: see if substances (markers) associated with oxidative stress and inflammation are increased in individuals with CBSDH see if the levels of these markers relate to the levels of homocysteine see if the levels of these markers decrease with short-term taurine supplementation see how bood vessels and platelets (small substances in the blood that help blood clot) work in individuals with CBSDH, if their ability to work is related to levels of markers of oxidative stress and inflammation, and if taurine supplementation improves how they work see if alterations of bone strength are related to levels of markers of inflammation. The hypotheses to be investigated are as follows: Biomarkers of oxidative stress and inflammation are increased in individuals with CBSDH The degree of elevation of the biomarkers of oxidative stress and inflammation is relative to the degree of elevation of homocysteine, the main accumulating substance for this disease. Treatment with taurine mitigates the elevation of biomarkers of oxidative stress and inflammation. Endothelial function (blood vessel function) is abnormal in individuals with CBSDH even when receiving standard therapy and is improved with taurine supplementation. Chronic platelet aggregation, a variable finding in individuals with CBSDH, is mitigated with taurine supplementation. Decreased bone mineral density relates to the increase in inflammatory markers in CBSDH. In addition, baseline pharmacokinetics (how much taurine is in the blood) of oral pharmacologic doses of taurine will be developed.

Official Title
-----------------
Oxidative Stress Markers In Inherited Homocystinuria And The Impact Of Taurine

Conditions
-----------------
Homocystinuria

Intervention / Treatment
-----------------
* Drug: taurine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A confirmed biochemical, molecular, or enzymatic diagnosis of classic homocystinuria due to cystathionine beta-synthase deficiency (OMIM 236200) And not fully responsive to therapy (eg, total homocysteine (tHcy) levels above 50 µmol/L on therapy including on B6 therapy) Be over 8 years old and less than 50 years. The first four patients will be adults (age 18-50 years) Be able and willing to provide informed consent Exclusion Criteria: Pregnancy: Females who are pregnant or lactating will be excluded from the study as the influence of pregnancy on the markers is not known nor is the safety of taurine supplementation in pregnancy. Continued antioxidant intake: Individuals currently taking taurine, over the counter energy drinks containing taurine or other high dose antioxidants and unwilling to discontinue this for the study period (including a 2 week wash out period) will be excluded as such intake will likely impact laboratory results. Individuals taking Vitamin C as a prescribed treatment for their homocystinuria will be excluded as the antioxidant therapy may impact antioxidant and inflammation markers. (As Vitamin C is not standard of care for this disease we anticipate this to have minimal impact on recruitment.) Individuals currently taking platelet aggregation inhibitors such as salicylate on a self prescribed basis and unwilling to discontinue this for the study period (including a washout period of at least two weeks prior to the study) will be excluded as salicylate intake will impact platelet study results. Individuals taking salicylate (or other platelet aggregation inhibitors) prescribed as a therapy for their homocystinuria or other health issues will not be asked to stop the medication. They will participate in the study, but will be excluded only from the platelet studies. Medication interactions: Individuals unable or unwilling to abstain from use of cyclic guanosine monophosphate (cGMP) phosphodiesterase 5 inhibitors (such as Viagra) during the study period will be excluded from the nitroglycerin-induced flow-mediated dilatation studies in accordance with known labeling contraindications. Inflammatory status: Individuals who have a significant chronic illness that has a marked inflammatory component will be excluded from the study as the illness will impact inflammatory markers. Patients with an acute illness, which may impact inflammatory biomarkers, will be postponed for study entry until the acute illness is resolved. Entry into the study at a later day will be offered. Recent cardiovascular event. Cardiovascular events (stroke, myocardial infarct, deep vein thrombosis, pulmonary embolus, thrombosis, or uncontrolled hypertension) may interfere with platelet function studies and with various mediators during the first months after the event. Patients who had such an event within the last 6 months will be excluded. Hypertriglyceridemia. Individuals with a triglyceride level above 300 mg/dl will be excluded from the study. Informed consent: Individuals who are unwilling or unable to consent, or in the case of minors who are unwilling or unable to assent will be excluded due to lack of ability to ensure informed consent. Study compliance and integrity: Individual who anticipate an inability to comply with study procedures and requirements will be excluded. -

Ages Eligible for Study
-----------------
Minimum Age: 8 Years
Maximum Age: 49 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Taurine<br>Treatment with Taurine | Drug: taurine<br>* Take Taurine for 4 1/2 days, two doses per day<br>* Other names: Not Applicable. No other names.;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Thiobarbituric Acid Reactive Substances (TBARS) in Individuals With Cystathionine Beta Synthase Deficient Homocystinuria (CBSDH) Pre and Post Taurine Treatment. | TBARS were measured in plasma via colorimetric absorbance. TBARS are a marker of oxidative stress. They are formed as a by-product of lipid (fat) oxidation. TBARS predominantly reflect the level of malondialdehyde (MDA) a substance that is formed from the breakdown of polyunsaturated fatty acids. | Baseline and after 4 days of therapy. | 
| Difference in Tumor Necrosis Factor Alpha (TNF-alpha) in Individuals With CBSDH Pre and Post Taurine Treatment. | TNF-alpha was measured in plasma via Luminex high sensitivity assay. TNF-alpha is a signaling protein, or cytokine that promotes an inflammatory response. | Baseline and after 4 days of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Endothelial Function (Blood Vessel Function) in Individuals With CBSDH Pre and Post Taurine Treatment | Endothelial function was measured by doppler brachial artery flow-mediated dilation (FMD) studies. | Baseline and after 4.5 days of taurine treatment | 
| Difference in Endothelial Function (Blood Vessel Function) in Individuals With CBSDH and Homocysteine Levels Greater Than 125 Micromole/L Pre and Post Taurine Treatment. | Endothelial function was measured by doppler brachial artery flow-mediated dilation (FMD) studies. | Baseline and after 4.5 days of therapy. | 
| Difference in Endothelial Function (Blood Vessel Function) in Individuals With CBSDH and Pre Taurine Exposure FMD Values Less Than 10 mm Pre and Post Taurine Treatment. | Endothelial function was measured by doppler brachial artery flow-mediated dilation (FMD) studies. | Baseline and after 4.5 days of therapy. | 
| Percent of Individuals With Decreased Bone Mineral Density. | Bone mineral density was assessed via whole body dual energy X-ray absorptiometry (DEXA) with bone density corrected for age. The absolute DEXA value was not used for analysis, rather values below 2 standard deviations of normal were taken as evidence of osteoporosis. | Baseline | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cystathionine beta-synthase (CBS)