Phenylketonuria, Oxidative Stress, and BH4

Phase 2

Terminated

Brief Summary: The purpose of this study is to see how tetrahydrobiopterin therapy (BH4; also known as sapropterin dihydrochloride or Kuvan) affects measures of oxidative stress and endothelial function in patients with Phenylketonuria (PKU).

Detailed Description: Oxidative stress will be induced by having participants eat a meal in polyunsaturated fats. The investigators will see how participants respond to the meal challenge over the course of 6 hours.

* PKU participants who are currently on BH4 therapy will be evaluated while taking BH4 with the meal at a single study visit.

* PKU participants who did not responded to BH4 therapy will be evaluated twice. At the first study visit the investigators will see how you react to the meal challenge when you are not given BH4. You will be given BH4 for two weeks, then return for a second meal challenge study visit while taking BH4.

* Healthy controls will be evaluated after consuming the meal only (no BH4) at a single study visit.

Recruitment & Eligibility

Inclusion Criteria

Have read, understood, and signed this consent form (and assent form, if <18 years old)
Are between the ages of 10-45 years
Weigh at least 75 pounds (34 kg)
Meet group-specific criteria

Exclusion Criteria

Smoke
Have any history of cardiovascular disease
Have hepatic impairment, or demonstrate abnormal baseline liver function lab test results
Have donated blood within 3 months prior to the study or are anemic as shown by the baseline lab results
Are unwilling to discontinue dietary supplements (excluding medical food) two weeks prior to their first study visit
Are currently take medications that will interfere with the interpretation of selected endpoints (such as lipid-lowering medication)
Are currently pregnant or breastfeeding
Excluding PKU, have a chronic illness, disorder, or condition (including but not limited to diabetes, hypertension, cancer)
Have taken any investigational drug (including Kuvan for Kuvan-unresponsive participants & controls) within 3 months prior to the study
In the opinion of the Investigator, should not be included in the study for any reason, including inability to follow study procedures

Arm && Interventions

Group	Intervention	Description
BH4 Non-Responders	Kuvan	Participants in this group have PKU and were deemed unresponsive to the drug. They will attend their first study visit, and proceed through the meal challenge without BH4. They will then take BH4 for 2 weeks. The second meal challenge will be performed with the participant's final dose of BH4.
BH4 Non-Responders	Meal Challenge	Participants in this group have PKU and were deemed unresponsive to the drug. They will attend their first study visit, and proceed through the meal challenge without BH4. They will then take BH4 for 2 weeks. The second meal challenge will be performed with the participant's final dose of BH4.
Healthy Controls	Meal Challenge	Participants in this group match an enrolled PKU participant in terms of age, gender, and body mass index class. They will participate in a single study visit and will not be given BH4.
BH4 Responders	Meal Challenge	Participants in this group will use their already prescribed BH4 with the meal challenge and be assessed at a single study visit. They will take their prescribed BH4 with the meal.

Primary Outcome Measures

Name	Time	Method
C-Reactive Protein (CRP)	CRP will be measured every other hour for six hours at baseline (study visit 1) for all study groups and again during a second visit 2 weeks after baseline in BH4 Non-Responders only (study visit 2)	Markers will be assessed every other hour for each 6-hour study visit. Kuvan responders and healthy controls will only be assessed at one 6-hour study visit. Kuvan non-responders will be assessed at two study visits (a baseline visit, and a visit after two weeks of Kuvan therapy). Values will be assessed groupwise and also assessed for intrapersonal change in the Kuvan non-responsive group. Time frame of participation is estimated at one month.
Lipid Peroxidation	Lipid peroxidation will be measured every other hour for six hours at baseline (study visit 1) for all study groups	Markers will be assessed every other hour for each 6-hour study visit. Kuvan responders and healthy controls will only be assessed at one 6-hour study visit. Kuvan non-responders will be assessed at two study visits (a baseline visit, and a visit after two weeks of Kuvan therapy). Values will be assessed groupwise and also assessed for intrapersonal change in the Kuvan non-responsive group. Time frame of participation is estimated at one month.

Secondary Outcome Measures

Name	Time	Method