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The Anti Fibrotic Effect of Aramchol™ on Liver
Fibrosis in TAA Animal Model
INTRODUCTIONLiver fibrosis is the accumulation of collagen following chronic inflammation. The cascade of events leading to its formation begins with inflammatory stimuli, which further proceeds to the activation of quiescent stellate cells in the space of Disse to myofibroblast like cells, that secrete collagen. A range of inflammatory diseases can cause liver fibrosis including viral hepatitis, immune injury, and alcoholic and non-alcoholic steatohepatitis (NASH). TAA is well established model of experiment liver fibrosis in rodents. TAA is bioactivated in the liver via oxidative process leading to its S-oxidative and the highly reactive S,S-oxidative, which is presumably responsible for TAA hepatotoxicity. Use of TAA model is showing direct effect of liver fibrosis which is not through down regulation of steatosis and inflammation. While therapies for the underlying diseases leading to fibrosis have advanced, for example those for viral hepatitis, there are currently no approved therapies for treatment of fibrosis. Aramchol™ (arachidyl amido cholanoic acid) is a fatty acid-bile acid conjugate which has been shown to reduce liver fat content and collagen accumulation in several NASH models and is presently in a Phase 2b study for NASH treatment ARREST (NCT02279524).
CONCLUSIONS
• Aramchol™ down regulates cirrhosis in TAA animal model – macroscopic evaluation. Down regulation was dose dependent and significant at 5mg/kg.
• Aramchol™ down regulates fibrosis in histological evaluation (Mason – Goldnerstaining). The reduction is dose dependent and is significant at 5mg/kg.
RESULTS
METHODLiver fibrosis was induced by intraperitoneal injections of TAA (100mg/ml) atA dose of 20mg/100g body weight twice weekly for up to 10 weeks. Ratswere treated orally by gavage with Aramchol™ (1 and 5 mg/kg/day) orvehicle. Control TAA induced fibrosis were also treated with vehicle for thesame duration. At the end of the experiment, liver samples were obtained. Ahistological assessment of the livers was performed after staining withhematoxylin-eosin (H&E) and Mason trichrome staining. Evaluation offibrosis was based on the Ludwig and Batts staining system using thefollowing parameters: portal fibrosis (stage 1) characterized by mild fibrousexpansion of portal tracts; periportal fibrosis (stage2) showing fine strandsof connective tissue in Zone 1 with only rare portal-portal septa; septalfibrosis (stage 3) manifested by connective tissue bridges that link portaltracts with other portal tracts and central veins but not regenerative nodules;and cirrhosis (stage 4) showing bridging and nodular regeneration.
CONTACT INFORMATIONProf. Shimon Reif , Gastroenterologist and head of Pediatric Department at Hadassah Medical centers the Hebrew university Jerusalem: [email protected].
AIMThe aim of this study was to investigate the anti fibrotic effect of Aramchol™ using the Thioacetamide (TAA) rat model of fibrosis.
REFERENCES1. Abramovitch S, Sharvit E, Weisman Y, et al. Vitamin D inhibits
development of liver fibrosis in an animal model but cannot ameliorate established cirrhosis. Am J Physiol Gastrointest Liver Physiol. 2015;308(2):G112-20. doi: 10.1152/ajpgi.00132.2013 [doi].
2. Liedtke C, Luedde T, Sauerbruch T, et al. Experimental liver fibrosis research: Update on animal models, legal issues and translational aspects. Fibrogenesis & tissue repair. 2013;6(1):19.
3. Traber PG, Chou H, Zomer E, et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PloS one. 2013;8(10):e75361.
4. Verbeke L, Mannaerts I, Schierwagen R, et al. FXR agonist obeticholicacid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep. 2016;6:33453. doi: 10.1038/srep33453 [doi].
ACKNOWLEDGEMENTSThis study was sponsored by Galmed Pharmaceuticals Ltd.
R. Golan-Gerstl1, M. Valitsky1, R. Oren1, E. Brazovski2, L. Hayardeny1, S. Shimon Reif*1
1The Liver Unit, Hadassah Medical Center, Jerusalem, Israel2The Pathology Department, Sourasky Medical Center, Tel Aviv, Israel
Effect of Aramchol™ on Liver Fibrosis – Microscopic Evaluation / Masson
Goldner Staining
TAA plus ARAMCHOL™ 5mg/kg
TAA plus ARAMCHOL™ 1mg/kg
TAA No Treatment
Treatment with ARAMCHOL™ significantly prevents TAA induced fibrosis in a dose
dependent manner.
EXPERIMENTAL DESIGN – PREVENTIVE TREATMENT
Aramchol™
TAA
10 weeks
Effect of Aramchol™ on Liver Cirrhosis – Macroscopic Evaluation
Saline Control
TAA (20mg/100 gr body weight) twice per week during 10 weeks.
TAA + Aramchol™ 1 mg/kg
TAA + Aramchol™ 5 mg/Kg
Treatment with ARAMCHOL™ significantly prevents TAA induced cirrhosis.
Effect of Aramchol™ on Liver Fibrosis –Microscopic Evaluation Score 0-4
Treatment with ARAMCHOL™ significantly prevents TAA induced fibrosis.
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5
Saline TAA TAA + Aramchol1mg/Kg
TAA + Aramchol5mg/Kg
Positive Control5mg/Kg
Fib
rosi
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