Hepatocyte Transplantation for Phenylketonuria
Trial ID: NCT01465100
Status: TERMINATED
Study type: INTERVENTIONAL
Phase: PHASE1; PHASE2
Start date: 2011-10-12
Completion date: 2016-06-17
Sponsor: Ira Fox
Conditions: Phenylketonuria
Interventions: Preparative Radiation Therapy; Hepatocyte Transplant; Immunosuppression; Liver Evaluation; Neuro-psychological Assessment; Whole body Phe oxidation testing; Liver Biopsy
Locations: UPMC Children's Hospital of Pittsburgh
Countries: United States
Enrollment: 1
Age range: 14 Years - 55 Years
Sex: ALL

Summary:
Human phenylketonuria (PKU) results from phenylalanine hydroxylase (PAH) deficiency, and represents one of the most common and extensively studied single-gene Mendelian disorders in humans. Unfortunately, optimum clinical outcome demands lifelong dietary restriction through adherence to an unpalatable and expensive artificial diet. Challenges in maintaining traditional therapy lead to increasing phenylalanine (Phe) levels in patients as they approach adulthood with an incumbent severe burden of psychosocial and intellectual difficulties. The recent introduction of the new medication Sapropterin for treatment of PKU has improved Phe control and dietary tolerance in some patients, but at enormous cost to patients and insurers for the FDA designated orphan product. Thus, there is an unmet need for novel therapies to correct PKU. PAH is almost exclusively expressed in the liver in humans. The main objective of the current proposal is to examine the safety and efficacy of hepatocyte transplantation in patients with PKU.

Eligibility criteria:
Inclusion Criteria:

1. Previous diagnosis of classical PKU, as determined by a PAH mutation known to cause classical PKU, or a Phe \>20 mg/dL at any time.
2. Patients must have poor control on standard therapy (i.e. Kuvan or diet alone) as defined by two consecutive Phe levels of \> 12 mg/dL in the past six months. This is two times the recommended level. If the patient is being treated with Palynziq, they must discontinue treatment for at least two months before participating in this trial.
3. Baseline I.Q. ≥70 as assessed by Wechsler Abbreviated Scale of Intelligence (4-subtest IQ)
4. Must have a complete evaluation, including dietary records, in a PKU clinic in the past twelve months
5. Age between 14 and 55 years
6. Stated willingness to comply with all study procedures and availability for the duration of the study
7. Sexually active female subjects must agree to use two highly effective forms of contraception for the duration of the study

Exclusion Criteria:

1. I.Q. \<70
2. Known biopterin synthesis defects
3. Subject has active malignancy
4. Subject has known allergy or other contraindication to immune suppression medications (and their alternatives) required post transplant for the prevention of rejection
5. Subject has sepsis, pneumonia, other active infection, or other secondary life-threatening organ dysfunction at Screening or Baseline Visits. Subject may be re-screened once infection has cleared.
6. Subject is pregnant or breastfeeding
7. Subject has positive HIV serostatus
8. Liver biopsy shows significant fibrosis, defined by the Ishak Stage 5: bridges with occasional nodules, or higher. Liver biopsy will be performed if, in the clinical judgment of the investigators, subject has clinical signs of liver failure, or increased risk of liver fibrosis.
9. Any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or not completing the required study follow-up
10. Concurrent disease or condition that would interfere with study participation or safety

Outcomes:
Improvement/reversal of characteristics of PKU