LIVER REPOPULATION FOR LIVER INJURY AND GENE THERAPY

Project: Research project

Project Details

Description

Hepatocyte transplantation has an immense potential for gene therapy and
for treating acute liver failure. Because hepatocytes possess the cellular
machinery to express a variety of genes, their use for ex-vivo gene
therapy is particularly attractive. Similarly, hepatocyte transplantation
should provide novel therapies for acute liver failure, which currently
results in unacceptable mortalities of greater than 80%. Although
orthotopic liver transplantation can be employed in acute liver failure,
this is a formidable and irreversible procedure. In contrast, advantages
of hepatocyte transplantation include its technical simplicity, the
possibility of transplanting cells prepared from a single liver into
multiple recipients and the potential to cryopreserve and transplant cells
at a short notice. However, despite a great urgency in applying hepatocyte
transplantation in humans, a better understanding of the biology of
transplanted hepatocytes is required for an optimal usage. We hypothesize that the success of hepatocyte transplantation requires a)
identification of permissive conditions for hepatocyte survival and
function, b) identification of methods to increase the mass of
transplanted hepatocytes, and c) optimization of the time and dose of
cells required for therapeutic applications. To begin addressing these
critical issues, we developed novel systems with genetically marked
hepatocytes to unequivocally distinguish between transplanted and host
cells. Also, we demonstrated that transplanted hepatocytes survive and
function most optimally in the liver. We now propose to examine mechanisms
regulating proliferation and fate of transplanted hepatocytes in liver. We
will examine the proliferative capacity of transplanted hepatocytes and
determine whether use of liver regenerative stimuli could augment the mass
of transplanted hepatocytes. As transplantation of hepatocytes into the
liver may be limited by the capacity of the hepatic vascular bed, we will
determine the safety of hepatocyte transplantation. Using insights derived
from these studies, we will develop strategies for massive reconstitution
of the host liver. These strategies will be tested in powerful animal
models of genetic metabolic disease. Also, animal models of acute liver
failure will be used to define the timing, dose and value of hepatocyte
transplantation, a well as simultaneous administration of hepatic growth
factors. Finally, hepatocyte precursor cells will be used to determine
their value compared with primary hepatocytes. Completion of these
proposed studies will greatly advance our fundamental knowledge of
hepatocyte transplantation and help move this technology from the
laboratory to the bedside.
StatusFinished
Effective start/end date6/20/944/30/09

ASJC

  • Medicine(all)