Smith-Lemli-Opitz Syndrome and Cholic Acid

People with SLOS have a deficiency of the 7-dehydrocholesterol reductase enzyme that makes
cholesterol. Consequently, they exhibit deficient cholesterol levels and increased
cholesterol precursor lipids, which are thought to be toxic. Cholesterol itself normally
regulates the cholesterol synthesis pathway in the body and under conditions of low serum
cholesterol seen in SLOS, more of the toxic cholesterol precursors are made. Since
cholesterol is also necessary for production of bile acids in the liver, which help digest
dietary cholesterol from the intestine, it is likely that low cholesterol levels in SLOS
impairs bile acids from being made, which in turn prevents dietary cholesterol from being
absorbed properly and contributes to the cholesterol deficiency seen in SLOS. Raising serum
cholesterol in SLOS people by improving its absorption from the diet is expected to decrease
the potentially toxic cholesterol precursor lipids, and both changes would be theoretically
beneficial for SLOS people.

The objective of this study is to determine whether treatment with cholic acid (a major bile
acid made in the body that improves fat absorption) will increase dietary absorption of
cholesterol, reverse serum cholesterol deficiency, and reduce harmful cholesterol precursor
lipids. These changes would be favorable for SLOS people. To accomplish this objective, SLOS
participants will be given dietary cholic acid (brand name Cholbam, manufactured by
Retrophin) for 8 weeks and serum cholesterol and its precursor lipids will be measured before
and while taking the drug.

SLOS participants who are between 2 years and 25 years of age and are taking supplemental
dietary cholesterol for at least 3 months will be enrolled. Participants must be clinically
stable and able to travel to a study site. No change in supplemental dietary cholesterol
intake will be allowed during the study, and dietary records will be obtained throughout the
study.

To qualify for cholic acid therapy, participants must have two measurements of serum
cholesterol ≤100 mg/dl within one month before starting cholic acid. Participants will be
treated with cholic acid for 8 weeks and will have blood specimens drawn at baseline (day 0),
4-weeks, 8-weeks and 12 weeks (4 weeks after stopping cholic acid therapy).

Inclusion Criteria:

- Ages 2-25 years.

- Participants (or their parents/legally-authorized representative) must provide signed
informed consent.

- Assent must be obtained from those participants ages 7-17 years who are intellectually
capable of understanding this study.

- Diagnosis of SLOS based on clinical features and biochemical + genetic confirmation.

- Participants are capable of traveling to the STAIR study site.

- Fasting serum cholesterol ≤100 mg/dL on at least 2 specimens, each obtained at least 2
weeks apart during the Qualification Phase must be established before starting cholic
acid therapy.

- Clinically stable at the time of enrollment

- Participants must be on a constant dietary cholesterol intake for at least 3-months
prior to treatment with cholic acid.

- Participants must agree to make no changes in cholesterol supplementation during the
STAIR study.

- SLOS participants who are taking antioxidants will be included. Participants must
agree to make no changes in the antioxidant dose during this study.

- For females of childbearing age (who have begun menstruating), a negative pregnancy
test must be documented at the start of the study (week 0/ baseline) and at the end of
cholic acid administration (week 8).

Exclusion Criteria:

- Participants are unable to provide signed informed consent and/or verbal assent.

- Participants have an unstable clinical condition that would prevent completion of the
study. Medically unstable participants would include those with severe liver disease,
complex birth defects such as severe heart disease or renal dysplasia, those with
severe respiratory compromise requiring tracheostomy, or those who are not likely to
survive longer than 1 year.

- Participants are taking drugs, nutraceuticals, probiotics or other compounds that are
known or suspected to affect sterol metabolism.

- Participants have transaminase elevations (>3-fold above the reference range) at
baseline.