Liver Cell Transplant for Phenylketonuria

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by University of Pittsburgh
Information provided by (Responsible Party):
University of Pittsburgh Identifier:
First received: October 20, 2011
Last updated: September 24, 2014
Last verified: September 2014
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 Intervention Phase
Radiation: Preparative Radiation Therapy
Procedure: Hepatocyte Transplant
Drug: Immunosuppression
Other: Liver Evaluation
Behavioral: Psychological Assessment
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Hepatocyte Transplantation for Phenylketonuria

Resource links provided by NLM:

Further study details as provided by University of Pittsburgh:

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

Secondary Outcome Measures:
  • Engraftment of Hepatocytes [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    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.)

  • Engraftment of Hepatocytes [ Time Frame: up to one year ] [ Designated as safety issue: Yes ]
    Laboratory tests of hepatic function

Estimated Enrollment: 10
Study Start Date: December 2011
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Previous diagnosis of classical PKU (Phe >20 mg/dl) Phe level greater than 10 mg/dl in past 6 months or any measure of Phe >20 mg/dl in past 6 months.
  2. Psychological assessment in the past year
  3. I.Q. >70 as assessed by Wechsler Abbreviated Scale of Intelligence (2-subtest IQ)
  4. Must have careful dietary management for one month in PKU clinic.

Exclusion Criteria:

  1. I.Q. <70
  2. No biopterin synthestase defects
  3. Subject has active malignancy.
  4. Subject has allergy to immune suppression medications that are required post transplant procedure for the prevention of rejection.
  5. Subject has sepsis, pneumonia, other active infection or secondary life-threatening organ dysfunction.
  6. 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.
  7. Subject is pregnant or breastfeeding.
  8. Subject has positive HIV serostatus.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01465100

Contact: Rachel Sada, MS 412-692-7673
Contact: Maria Bond 412-692-7133

United States, Pennsylvania
Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center Recruiting
Pittsburgh, Pennsylvania, United States, 15201
Contact: Rachel E Sada, MS, CIP    412-692-7673   
Contact: Maria Bond    412-692-7133   
Principal Investigator: Ira J Fox, MD         
Sub-Investigator: Kyle Soltys, MD         
Sub-Investigator: George Mazariegos, MD         
Sub-Investigator: Rakesh Sindhi, MD         
Sub-Investigator: Geoffrey Bond, MD         
Sub-Investigator: Gerard Vockley, MD         
Sub-Investigator: Georgianne Arnold, MD         
Sub-Investigator: John Crowley, MD         
Sub-Investigator: Melvin Deutsch, MD         
Sub-Investigator: Ben Shneider, MD         
Sub-Investigator: Robert Squires, MD         
Sub-Investigator: Charles Fitz, MD         
Sub-Investigator: David Finegold, MD         
Sub-Investigator: Suneeta Madan-Kheterpal, MD         
Sub-Investigator: Robert Stough, MD         
Sub-Investigator: Diana Shellmer, PhD         
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15201
Contact: Rachel E Sada, MS    412-692-7673   
Contact: Maria Bond    412-692-7133   
Sponsors and Collaborators
University of Pittsburgh
Principal Investigator: Ira J Fox, MD University of Pittsburgh
  More Information

Responsible Party: University of Pittsburgh Identifier: NCT01465100     History of Changes
Other Study ID Numbers: PRO10100525 
Study First Received: October 20, 2011
Last Updated: September 24, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Pittsburgh:

Additional relevant MeSH terms:
Amino Acid Metabolism, Inborn Errors
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Genetic Diseases, Inborn
Metabolic Diseases
Metabolism, Inborn Errors
Nervous System Diseases processed this record on April 27, 2016