Hepatocyte Transplantation for Liver Based Metabolic Disorders

Lead Sponsor: Ira Fox

The purpose of this research study is to determine whether partial irradiation of the liver and liver cell transplantation can provide help for patients with life-threatening liver-based metabolic diseases who are unlikely to survive without extensive medical therapy or transplant. The goal of this research study is to determine if liver cell transplants can be effective as an alternative to organ transplantation. At the present time, liver cell transplants are experimental and have been done in a limited number of human subjects.

Management of patients with hepatic failure and liver-based metabolic disorders is complex and expensive. Hepatic failure results in impaired coagulation, altered consciousness and cerebral function, a heightened risk of multiple organ system failure, and sepsis. Liver transplantation is often the only available treatment option for severe, even if transient, hepatic failure. Patients with life-threatening liver-based metabolic disorders similarly require organ transplantation even though their metabolic diseases are typically the result of a single enzyme deficiency, and the liver otherwise functions normally. More than 17,000 patients currently await liver transplantation in the United States, a number that seriously underestimates the number of patients that need treatment, as it has been estimated that more than a million patients in the United States could benefit from transplantation. Unfortunately, use of whole liver transplantation to treat these disorders is limited by a severe shortage of donors and by the risks associated with major surgery. Hepatocyte transplantation holds great promise as an alternative to organ transplantation for the treatment of liver diseases, and numerous studies in rodents indicate that transplants consisting of isolated liver cells can correct various metabolic deficiencies of the liver and can reverse hepatic failure. The transplant procedure, which involves injection of isolated hepatocytes into the liver through the portal vein, is far less intrusive than transplantation of the whole liver and could be performed on severely ill patients with relatively low risk. In the presence of normal host liver architecture, the transplanted cells integrate into the host liver, providing considerable restorative potential. Because the native liver is not removed, the transplanted hepatocytes need only improve some of the functions of the failing liver and need not replace all hepatic functions. Although clinical trials of hepatocyte transplantation have demonstrated the long-term safety of the procedure, only partial correction of metabolic disorders has been achieved, and the degree to which donor hepatocytes have restored failing livers has not been adequate to circumvent the need for organ replacement.

• Metabolic Diseases

Intervention Type: Drug

Intervention Name: human hepatocyte transplantation

Description: Transplantation of hepatocytes into the liver will be through the portal vein. The portal vein will be accessed transhepatically, by umbilical vein, or surgically by a peripheral mesenteric vein. The subject will be evaluated de novo and if they are a candidate for orthotopic liver transplantation they will receive the transplant. Even if the subject receives the hepatocyte transplant and it does not work, they will be evaluated for orthotopic liver transplantation as if they never received the hepatocyte transplant. If at 6 months we see an improvement in disease, we will recommend a re-transplantation with a goal of complete correction of disease and until the subject is no longer required to be a candidate for organ transplantation. Subjects will be re-evaluated every 6 months for re-transplantation. Subjects will remain on the waiting list for organ transplantation. Further radiation therapy will not be needed prior to re-transplantation.

Arm Group Label: Hepatocyte Transplantation

Other Name: hepatocyte transplant

Intervention Type: Radiation

Intervention Name: Preparative Radiation Therapy

Description: Just prior to the hepatocyte transplant, a portion of the right hepatic lobe comprising between 35-50% of the entire liver volume will be irradiated to a dose of 7.5-10 Gy in a single fraction using a linear accelerator-based stereotactic radiosurgery system with intensity-modulated radiation therapy planning (IMRT).

Arm Group Label: Hepatocyte Transplantation

Criteria:

Inclusion Criteria: - Patients will have life-threatening liver-based metabolic disorders who are candidates for organ transplantation where hepatocyte transplantation is considered theoretically curative. - In addition to child subjects less than 18 years of age, for purposes of this protocol, adults up to age 21 years will be enrolled since this is the upper age limit of patients which are seen at Children's Hospital of Pittsburgh. Exclusion Criteria: - Patients with liver based metabolic disorders not theoretically treatable with organ transplantation. - Subjects who meet any of the following criteria will be excluded from participation in this protocol: 1. Subject has active malignancy. 2. Subject has allergy to immunosuppression medications that are required post transplant procedure for the prevention of rejection. 3. Subject has sepsis, pneumonia, other active infection or other secondary life-threatening organ dysfunction. 4. Significant liver fibrosis determined by biopsy (if clinically indicated). Significant liver fibrosis will be defined by the Ishak Staging, Stage 5: bridges with occasional nodules. 5. Subject is pregnant or breastfeeding.

Gender: All

Minimum Age: N/A

Maximum Age: 21 Years

Healthy Volunteers: No

United States

January 2020

Type: Sponsor-Investigator

Investigator Affiliation: University of Pittsburgh

Investigator Full Name: Ira Fox

Investigator Title: Professor of Surgery

• Urea Cycle Disorders
• Carbamoyl-Phosphate Synthase I Deficiency Disease
• Citrullinemia
• Ornithine Carbamoyltransferase Deficiency Disease
• Crigler-Najjar Syndrome

• Metabolic Diseases

Label: Hepatocyte Transplantation

Type: Experimental

Description: See Below

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)