Liver Cell Transplant for Phenylketonuria

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.

Conditions

• Phenylketonuria

Interventions

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

Transplantation of hepatocytes into the liver will be through the portal vein, either accessed transhepatically, or by umbilical vein. After cell transplantation, measures will be taken to provide chronic access to the portal venous circulation system. If chronic access is achieved, patients will be seen in the PCTRC once a week to assess the site. Hepatocytes from more than one donor may be required to provide sufficient numbers of cells for transplantation to correct the disease process and to optimize Phe tolerance. Hepatocytes will be infused until the goal number of hepatocytes is infused. If viable hepatocytes remain after the goal number has been infused, the remaining cells will also be infused, as tolerated by the patient.

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, EKG, chest x-ray, and abdominal ultrasound to assess blood flow to the blood vessels in the liver. A liver biopsy may be performed if, in the clinical judgment of the investigators, the subject shows clinical signs of liver failure, or is at increased risk for liver fibrosis.

BEHAVIORAL

Neuro-psychological Assessment

Subjects will undergo a repeat neuropsychological assessment at 6, 12 and 24 months post-transplant (Visits 4 and 6 and the End of Study Visit) which will be compared to results obtained pre-transplant to determine whether an improvement in assessment scoring is associated with the transplant procedure.

DIAGNOSTIC_TEST

Whole body Phe oxidation testing

Patient will again be asked to not eat or drink for at least four hours prior to testing. Isotopic monitoring of whole body Phe oxidation will be performed pre-transplant and at every follow-up visit following the final hepatocyte infusion. An additional Phe oxidation test may also be completed in the event of suspected graft rejection.

PROCEDURE

Liver Biopsy

Liver biopsies will be performed at 3 and 12 months post-transplant to assess for the presence of donor hepatocytes, and may be completed in the event of suspected graft rejection.

Sponsors & Collaborators

• Ira Fox

  lead OTHER

Principal Investigators

• Ira J Fox, MD · University of Pittsburgh

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

14 Years

Max Age

55 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2011-10-12

Primary Completion

2015-08-21

Completion

2016-06-17

FDA Drug

Yes

Countries

• United States

Study Locations