Liver Cell Transplant for Phenylketonuria

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01465100
Recruitment Status : Suspended (seeking additional funding)
First Posted : November 4, 2011
Last Update Posted : January 19, 2018
Information provided by (Responsible Party):
Ira Fox, University of Pittsburgh

Brief Summary:
The purpose of this research study is to determine whether partial irradiation of the liver and liver cell transplantation can reduce the need for dietary and medical management or could possibly eliminate the need for a special diet and medications to treat this disease for patients with phenylketonuria (PKU) by normalizing phenylalanine levels in the body. Phenylalanine (Phe) is a substance needed in the body that can only be obtained from the foods people eat. People with PKU cannot get rid of Phe in their body. Large amounts of Phe can cause problems, such as deterioration of mental function. At the present time, liver cell transplants are experimental and have been done in only a limited number of human subjects.

Condition or disease Intervention/treatment Phase
Phenylketonuria Radiation: Preparative Radiation Therapy Procedure: Hepatocyte Transplant Drug: Immunosuppression Other: Liver Evaluation Behavioral: Psychological Assessment Phase 1 Phase 2

Detailed Description:
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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hepatocyte Transplantation for Phenylketonuria
Study Start Date : December 2011
Estimated Primary Completion Date : October 2018
Estimated Study Completion Date : January 2019

Arm Intervention/treatment
Experimental: Hepatocyte Transplantation
See Below.
Radiation: Preparative Radiation Therapy
Subjects will undergo CT-based simulation and treatment planning for radiation therapy. Once a suitable hepatocyte donor is found and the cell count and viability is acceptable for transplantation, patients will receive Intensity-Modulated Radiation Therapy (IMRT) in one fraction(10 Gy)to the right lobe of the liver (but not exceeding 50% of the liver mass).

Procedure: Hepatocyte Transplant
Within a maximum of two days after hepatic irradiation,the right or main portal vein will be occluded transiently (60-90 min)to provide a compensatory mitotic signal to donor hepatocytes. Directly following this transient occlusion of the portal vein, donor hepatocytes will be transplanted into the irradiated portion of the recipient's liver. If at 6 months we see an improvement in PHE tolerance but not normalization (i.e. PHE levels from 6 mg/dl to 10 mg/dl) on an unrestricted PHE diet, we will recommend re-transplantation with a goal of complete correction of PKU. Subjects will be re-evaluated every 6 months for re-transplantation.

Drug: Immunosuppression
Following transplantation, patients will be treated with conventional immune suppression, as is used following whole organ liver transplantation. Patients will be followed as routinely performed following organ transplantation and also followed as would normally be performed for their PKU.

Other: Liver Evaluation
Prior to the hepatocyte transplant subjects will undergo a liver evaluation which is standard for all patients who have whole organ transplants at Children's Hospital of Pittsburgh of UPMC. The evaluation includes immunosuppression medication education, psychological assessment, bloodwork to assess blood count, blood and tissue type, blood chemistries, immune system function and certain infectious diseases and abdominal ultrasound to assess blood flow to the blood vessels in the liver.

Behavioral: Psychological Assessment
Subjects may undergo a psychological assessment at least 6 months post-transplant which will include a semi-structure open ended interview as well as the Adaptive Behavior Assessment System-II assessment and Beck Depression Inventory. If subjects undergo these assessments, they will be compared to those obtained pre-transplant to determine whether an improvement is associated with the transplant procedure. In addition, if subjects are experiencing depression, they will be referred for further care.

Primary Outcome Measures :
  1. Improvement/reversal of characteristics of PKU [ Time Frame: 6 months post hepatocyte transplant ]
    Measured as a 50% decrease in Phe from baseline study level.

Secondary Outcome Measures :
  1. Engraftment of Hepatocytes [ Time Frame: 6 months ]
    Liver biopsy samples may be obtained if a response is ascertained after 6 months. (The approach used, surgical vs percutaneous needle biopsy, will be determined by the clinical setting.)

  2. Engraftment of Hepatocytes [ Time Frame: up to one year ]
    Laboratory tests of hepatic function

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Ages Eligible for Study:   14 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01465100

United States, Pennsylvania
Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15201
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15201
Sponsors and Collaborators
Ira Fox
Principal Investigator: Ira J Fox, MD University of Pittsburgh

Responsible Party: Ira Fox, Professor of Surgery, University of Pittsburgh Identifier: NCT01465100     History of Changes
Other Study ID Numbers: PRO10100525
First Posted: November 4, 2011    Key Record Dates
Last Update Posted: January 19, 2018
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Ira Fox, University of Pittsburgh:

Additional relevant MeSH terms:
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases