Hepatocyte Transplantation for Liver Based Metabolic Disorders

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.

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.