Oxidative Stress Markers In Inherited Homocystinuria And The Impact Of Taurine

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:

1. see if substances (markers) associated with oxidative stress and inflammation are
increased in individuals with CBSDH

2. see if the levels of these markers relate to the levels of homocysteine

3. see if the levels of these markers decrease with short-term taurine supplementation

4. 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

5. 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.

Inclusion Criteria:

1. A confirmed biochemical, molecular, or enzymatic diagnosis of classic homocystinuria
due to cystathionine beta-synthase deficiency (OMIM 236200)

2. And not fully responsive to therapy (eg, total homocysteine (tHcy) levels above 50
µmol/L on therapy including on B6 therapy)

3. Be over 8 years old and less than 50 years. The first four patients will be adults
(age 18-50 years)

4. Be able and willing to provide informed consent

Exclusion Criteria:

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. Hypertriglyceridemia. Individuals with a triglyceride level above 300 mg/dl will be
excluded from the study.

7. 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.

8. Study compliance and integrity: Individual who anticipate an inability to comply with
study procedures and requirements will be excluded.