HepaHope Product Publications

American Association for the Study of Liver Disease (AASLD)

October 27-31, 2006
BOSTON, USA

Assessment of a Novel Porcine Liver Slice-Filled Bio-artificial Liver (BAL) for Dialysis of Liver Failure Patients

Sung-Soo Park1, Jaeho Jung1, Delai Zhao1, Hyoung Yoon1, Jennifer Tam1, Young Park1, Charles Gropper1, Robert G. Gish2, Brendan M. McGuire3, Angela Panoskaltsis-Mortari4, Jae Jin Han5, Young-Suk Lim6, Han Chu Lee6, Dong-Jin Suh6

1HepaHope Inc, 2California Pacific Medical Center, 3University of Alabama, 4University of Minnesota,
5Ewha Womans University, 6University of Ulsan

Dialysis with a BAL may become a potential therapy for liver failure patients. With efficient toxin removal and biochemical function, the new HepaHope BAL is designed to treat such patients. The BAL contains porcine liver slices with multiple, native cell types in well-preserved structures that allow high capacity and efficient removal of toxins.

Several in vitro and in vivo 6 hour exposure BAL studies on animals designed to mimic clinical treatment conditions were conducted. In vitro studies examining ammonia (~1,000 µg/dL) clearance showed 1.12 ml/min/kg clearance. Clearance of nine drugs commonly administered to liver failure patients (Diazepam, Dopamine, Fentanyl, etc.) indicated a varied metabolism profile, with clearance ranging from 15 to 58% of initial dose. The efficacy and safety of the device has been examined in vivo on animals. The survival time of eight class A hounds (>50 lbs) with acute liver failure, induced by vascular occlusion, was determined in control and treated dogs using the BAL. Following separation from whole blood, their plasma was run through the BAL with either empty (4 control) or porcine slice filled (4 treated) slice cassettes. Dogs were treated for a total of 6 hours followed by a survival observation period up to 36 hours post occlusion. Results from the efficacy study demonstrated an average increased survival of 258% (control = 12.6 ± 3.8 hr, treated = 32.9 ± 6.3 hr; p<0.001). Averaged clinical biomarkers indicating liver toxicity were substantially improved between control and treated dogs during BAL treatment (e.g. AST=48-62%, ALT=34-47%, total bilirubin=24-39%, lactate= 49-81% of control; p<0.01, except lactate, p<0.05). Production of TNF-alpha, IL-6, MCP-1, C-reactive protein and serum amyloid A was quantitated and a lack of significant difference between control and treated group suggests there are no adverse systemic effects from porcine derived components.

Recent work has utilized designated pathogen free (DPF) and human membrane bound complement regulatory protein hCD46 transgenic pigs as a liver source. Clearance of ~1,000 µg/dL ammonia was 1.68ml/min/kg, suggesting superior ammonia clearance capacity of DPF transgenic pig liver compared to the liver from normal pig. Furthermore, the use of this genetically modified tissue may obvert inherent immune responses that are associated with the use of xenobiotic tissues for clinical therapy.

CONCLUSION: The favorable pre-clinical results have encouraged the Company in its feasibility studies with DPF hCD46 transgenic pigs for clinical trials with liver failure patients.