Oxidative Stress Markers In Inherited Homocystinuria And The Impact Of Taurine

University of Colorado Denver (CU Denver)

Status and phase

Completed

Phase 2

Phase 1

Conditions

Homocystinuria

Treatments

Drug: taurine

Study type

Interventional

Funder types

Other

Identifiers

NCT01192828

FDR003907 (Other Grant/Funding Number)

08-1376

Details and patient eligibility

About

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.

Full 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.

Enrollment

15 patients

Sex

All

Ages

8 to 49 years old

Volunteers

No Healthy Volunteers

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:
1. 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.
2. 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.)
3. 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:
1. 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.
2. 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.