HepaHope Product Publications
American Association for the Study of Liver Disease (AASLD)
October 31- November 4, 2008
San Francisco, USA
A Novel Acute Liver Failure Large Animal Model Suitable for Testing Extracorporeal Bio-artificial Liver Systems
Sung-Soo Park1, Jaeho Jung1, Delai Zhao1, Sunnie Kim1, Young Park1, Hyoung Yun1, Sam Lee1, Jun Park1, Yoonhee Hur1, Liam Reay1, Sunny Yang1, Jik Su Shin1, Jun Choi1, Chris Stevens1, Robert G. Gish2, Brendan M. McGuire3, Angela Panoskaltsis-Mortari4, Han Chu Lee5, Dong-Jin Suh5
1HepaHope Inc, 2California Pacific Medical Center, 3University of Alabama, 4University of Minnesota, 5University of Ulsan
Background and Purpose: Acute liver failure (ALF) patients often develop life threatening cerebral edema (CE) succumbing to cerebral herniation. Currently there is not a standard large animal model of ALF and CE suitable to test extracorporeal bio-artificial liver (BAL) systems for preclinical proof of concept. The objective of this study was to create a suitable large animal ALF model and evaluate the efficacy of the bio-artificial liver (BAL), HepaPheresis™ System developed by HepaHope, Inc.
Methods and Results: We explored three ALF models [hepatotoxin-acetaminophen, two-stage devascularization surgery, and combination surgery-toxin (CST)] in large animals. CST model developed using 45 dogs was most reproducible. It incorporated bolus injections of NH4Cl (1.0-7.5 mmol /20 kg dog weight) and a two stage hepatic devascularization procedure (portacaval shunt on day 1 followed by transient hepatic occlusion on day 3). From the final CST model, dogs developed increased intracranial pressure (ICP) >25 mmHg and elevations in other biomarkers indicative of ALF including AST/ALT (>10,000 IU/L), bilirubin (>0.6 mg/dL), ammonia (400-2,000 μg/dL), and INR (>6.5). Metabolic acidosis and hyperkalemia complications associated with CST were resolved by modifying occlusion time to 2 hours and 30 minutes and changing to bolus NH4Cl and NaHCO3 injections.
Once established the HepaPheresis™ System was tested to determine if treatment could impact cerebral edema of ALF with ICP as the endpoint measure. For enrollment, animals had to meet the following inclusion criteria:, ammonia (≥150 μg/dL), AST/ALT (≥1,000 IU/L), ALP (≥200 IU/L), K (≤5.5 mmol/L), pH (≥7.15), creatinine (≤2.0 mg/dL), and ICP (≥15%). The primary efficacy endpoint was an ICP slope change, defined as the difference between the estimated ICP slope before and after the treatment period in animals with established ALF. The ICP slope is estimated from a simple regression line. Animals were randomly assigned to either treatment (n=5) or control (n=5) groups with treated animals undergoing 6 hours of therapy with the HepaPheresis™ System. The ICP slope change in treated dogs was 4X less than control dogs at the end of the 6 hour treatment window.
Conclusion: A reproducible and reversible large animal model of ALF was established and demonstrated to be suitable for the evaluation of extracorporeal BAL Systems. Decreased ICP observed in BAL treated dogs compared with control animals suggesting a reduction in cerebral edema provides encouragement for the continued development of the HepaPheresis™ System for the treatment of ALF patients.
