Liver Cell Transplant for Phenylketonuria

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 determine the feasibility of hepatocyte
transplantation to correct the biochemical (and ultimately, clinical) features of PKU.

Inclusion Criteria:

Children (14-17 years of age)

1. Previous diagnosis of classical PKU as determined by Phe >20 mg/dl at diagnosis or a
PAH mutation known to cause classical PKU

2. Patients have poor control on standard therapy (i.e. Kuvan or diet alone) as defined
by two consecutive phe levels of > 12 mg/dl in past 6 months. This is nearly 4 times
the recommended level.

3. Baseline I.Q. >70 as assessed by Wechsler Abbreviated Scale of Intelligence (2-subtest
IQ)

4. Cognitive or psychological impairment as defined by a score of one standard deviation
below the mean in two of the four following assessments:

- Wechsler Intelligence Scale for Children-Fourth Addition-Coding Subtest (for
individuals up to 16 years, 11 months years of age) OR Wechsler Adult
Intelligence Test-Fourth Edition-Coding Subtest (for individuals 17 years of age)

- Behavior Rating Inventory of Executive Function (parent version)

- Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency

- BASC-II (Behavior Assessment System for Children-Second Addition)

5. Psychological assessment in the past year

6. Must have a complete evaluation including dietary records in PKU clinic. Thereafter,
monthly Phe levels will be drawn (per clinical care management for PKU patients) and
3-Day food records will be completed monthly until hepatocyte cells are available.

Adults (18 years of age and older)

1. Previous diagnosis of classical PKU as determined by Phe >20 mg/dl at diagnosis or a
PAH mutation known to cause classical PKU

2. Patients have poor control on standard therapy (i.e. Kuvan or diet alone) as defined
by two consecutive phe levels of > 12 mg/dl in past 6 months. This is double the
recommended level.

3. Psychological assessment in the past year

4. I.Q. >70 as assessed by any standardized and validated IQ measure.

5. Must have dietary documentation and a routine clinical evaluation in PKU clinic one
month prior to enrollment. Monthly Phe levels will be drawn (per clinical care
management for PKU patients) and 3-Day food records will be completed monthly until
hepatocyte cells are available.

Exclusion Criteria:

- I.Q. <70

- No biopterin synthestase defects

- Subject has active malignancy.

- Subject has allergy to immune suppression medications that are required post
transplant procedure for the prevention of rejection.

- Subject has sepsis, pneumonia, other active infection or secondary life-threatening
organ dysfunction.

- Liver biopsies, not necessarily a consideration for organ transplantation, but a
contraindication at this time to cell transplantation if significant fibrosis was
identified, may be performed if there is clinical indication of liver disease.
Significant liver fibrosis will be defined by the Ishak Staging, Stage 5: bridges with
occasional nodules.

- Subject is pregnant or breastfeeding.

- Subject has positive HIV serostatus.

- Inability to comply with research procedures.