Hepatocyte Transplantation for Acute Decompensated Liver Failure

Orthotopic liver transplantation has become the treatment of choice for patients with acute
liver failure with poor prognostic signs. Survival following hepatic transplantation has
improved in the last decade for a number of reasons. These include improvement in
immunosuppression, improved methods for preserving and transporting organs, use of donors
which had been previously considered unacceptable, use of reduced-sized grafts , and the use
of living-donor hepatic transplantation. Despite encouraging survival statistics, there
continues to be significant morbidity and mortality associated with hepatic transplantation.
In addition, the success of hepatic transplantation has broadened the indications for this
form of therapy without a concomitant increase in the number of donors available for these
patients.

Since the development of a method for isolating primary hepatocytes by collagenase perfusion,
many investigators have demonstrated the efficacy of hepatocyte transplantation in the
treatment of liver failure and inherited metabolic disorders in experimental animals.
Treatment of liver diseases with transplantation of isolated hepatocytes rather than the
whole liver has several theoretical advantages. Unlike the whole liver, isolated hepatocytes
could be cryopreserved for instant availability and could be modified genetically or
otherwise to enhance specific functions, stimulate proliferation or abrogate allograft
rejection. Hepatocyte transplantation should be less stressful than whole liver
transplantation because the host organ remains intact. Since the transplanted cells integrate
into the host liver, they could provide restorative potential and the consequences of graft
loss would be relatively minor. In addition, hepatocyte transplantation would not interfere
with subsequent liver transplantation, should that become necessary.

Inclusion Criteria:

- Subjects will include those patients with ALF who are potential conventional liver
transplant recipient candidates based on PELD criteria as well as those who would not
be considered candidates for orthotopic liver transplantation (e.g. patients who
appear to be too small or too ill for solid organ transplant or those who have a
diagnosis that is a contradiction for whole organ transplantation, for example,
systemic mitochondrial hepatopathy).

- If the patient is a candidate for orthotopic liver transplantation (per standard
clinical criteria), they will be officially listed for liver transplantation as well
as hepatocyte transplantation.

- If a subject is a potential conventional liver transplant recipient candidate and a
donor liver is available; the patient will receive a solid organ transplant.

- Subjects ages 0-21 years old will be included in this study.

Exclusion Criteria:

The patient has:

1. Severe cardiovascular or respiratory disease at baseline and at the time of hepatocyte
transplant as defined by

1. Central venous pressure >25 mm Hg or if known, pulmonary capillary wedge pressure
of >30 mg Hg or

2. Oxygen saturation of <90% on > 60% oxygen OR a P/F ratio (Po2/FiO2) of <1.

2. Hemodynamically significant gastrointestinal bleeding causing a systolic blood
pressure <70mmHg at the time of transplantation.

3. Uncorrectable coagulopathy despite use of plasmapheresis that would preclude any
invasive procedures.

4. Leukopenia at the time of cell transplant, defined as an absolute neutrophil count of
<500/µL.

5. Known allergy to immunosuppression medications that are required post transplant
procedure for the prevention of rejection.

6. Active malignancy except those with acute liver failure during treatment with
estimated life expectancies of >1 year if the malignancy is controlled.

7. Sepsis or other active infection except those without evidence of hemodynamically
significant uncontrollable systemic sepsis with positive blood or tissue cultures.

8. Intrauterine pregnancy. All females of childbearing potential will receive a pregnancy
test prior to enrollment.