HEPATOCELLULAR TRANSPLANTATION AND TARGETING GENETIC MARKERS TO HEPATIC CELLS 
I . SUMMARY 
Orthotopic liver transplantation (OLT) represents the only therapeutic option for 
many patients with end- stage liver disease as well as many inborn genetic errors of 
hepatic metabolism. Despite dramatic progress in methods for orthotopic liver 
transplantation, the utilization of this procedure is limited by its considerable 
morbidity and mortality, by a chronic shortage of organs for transplant, and by 
difficulty arranging funding for many patients. Many children with fulminant hepatic 
failure do not receive orthotopic transplantation because this technology is unavailable 
or unaffordable. Hepatocellular transplantation (HCT) , in which isolated, heterologous 
hepatocytes from a donor liver would be infused into the diseased organ in order to 
provide essential hepatic functions, could provide a much needed therapeutic alternative 
to orthotopic liver transplantation in the treatment of some causes of hepatic 
insufficiency. Experiments in animals have demonstrated that several genetic 
deficiencies of hepatic metabolism can be reversed by HCT including analbuminemia, 
hyperbilirubinemia (bilirubin, UDP-glucuronyl transferase deficiency) , and 
hypercholesterolemia (LDL-receptor deficiency) as well as experimentally induced hepatic 
failure. Despite this experience, HCT has never been attempted in human subjects. 
This protocol represents the first proposed clinical trial of HCT. We are proposing 
a clinical trial in which HCT would be attempted as a therapeutic intervention in 
children with acute hepatic failure who have no other medical or surgical options. This 
proposal is intended to establish surgical methods for HCT and to evaluate the 
feasibility of this procedure for treating hepatic disease in humans. It is our 
expectation that HCT may provide short-term support for patients awaiting organ 
availability, a "bridge to recovery" allowing patients with fulminant hepatic failure 
to recover, or a long-term repopulation of the patient's liver with healthy donor cells. 
One of the major limitations of many animal studies in HCT is that, since the donor 
hepatocytes are often indistinguishable from those of the host, it has often been 
difficult to demonstrate a clear correlation between engraftment and the therapeutic 
effect. In order to verify engraftment independent of the therapeutic response, we 
propose to "mark” the donor hepatocytes by transducing these cells with a recombinant 
retroviral vector (LNL6) carrying a marker gene (NEO-R, neomycin phosphoribosyl 
transferase) . The presence of this marker will enhance the ability to identify 
transplanted cells in the host using assays for the NEO-R gene or transcribed NEO-R 
mRNA. The LNL6 vector has been approved for human use and has been used as a marker 
gene for transplanted cells in human subjects without any reported adverse effects. 
The HCT portion of this protocol represents conventional clinical investigation 
which has been approved by the Institutional Review Boards for Human Research (IRB) and 
Institutional Biosafety Committees (IBC) committees at the Baylor College of Medicine 
(BCM) and Texas Children's Hospital (TCH) and would not normally be reviewed by the RAC. 
We would like to emphasize that this is a proposal with therapeutic intent. As such, 
we believe that the essential issues are those which regulate clinical research in 
general, namely; i) identification of patients for whom there are no other medical or 
Recombinant DNA Research, Volume 14 
