A Pilot Study to Develop a Model of Acute-on-Chronic Model of Liver Failure in Dog

Liver failure is a serious problem that carries a high mortality. Two common presentations of liver failure exist: acute liver failure (ALF) of previously healthy subjects, and acute-on-chronic liver failure of subjects with existing (cirrhotic) liver dis ease. These two presentations of liver failure share similarities such as acute loss of hepatocyte function. However, they differ considerably in incidence, etiology, manifestations, and mortality. Furthermore, they differ in the existence of a pre-clinic al model to evaluate new modes of therapy (animal models of acute liver failure exist, but a large animal model of acute-on-chronic liver failure does not). Promising new therapies exist, such as the bioartificial liver (BAL), to provide detoxification an d synthetic activity during recovery of liver injury, as a bridge to liver transplantation, or as a chronic supportive therapy. The BAL operates extracorporeally like hemodialysis, but is unique in that it contains metabolically active liver cells (i.e., hepatocytes). The broad, long term objective of our research program is to develop a cell-based extracorporeal BAL to support patients with acute and acute-on-chronic forms of liver failure. To this end, Dr. Nyberg's group have developed a novel BAL, the spheroid reservoir BAL (SRBAL), and initiated pre-clinical studies to establish its efficacy in a canine model of drug-induced ALF. Efficacy studies of the SRBAL in a large animal model of acute-on-chronic liver failure have been curtailed since such a mo del does not currently exist. Therefore, the goal of this application is to develop a large animal model of acute-on-chronic liver failure. The proposed new model will be used to evaluate the SRBAL in a subsequent pre-clinical study funded by an National institute of Health (NIH) grant. Demonstration of efficacy of the SRBAL using an animal model of acute-on-chronic liver failure will provide a scientific basis for advancement to human clinical trials.