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Why Animal Models of Human Disease?

Why Animal Models of Human Disease?. Gregory J. Gores, M.D. Pros Recapitulate disease process Allow genetic manipulation Allow pharmacologic studies Necessary for FDA approval processes. Cons Disease processes in animals and humans can be strikingly different

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Why Animal Models of Human Disease?

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  1. Why Animal Models of Human Disease? Gregory J. Gores, M.D.

  2. Pros • Recapitulate disease process • Allow genetic manipulation • Allow pharmacologic studies • Necessary for FDA approval processes • Cons • Disease processes in animals and humans can be strikingly different • Few large animal models due to expense • Drug metabolism is different • Models are time limited (days or months) vs. humans (years)

  3. Ideal Animal Model of PSC Would Display • Inflammatory bowel disease • Large bile duct strictures • Progression over time • Loss of bile ducts • Cirrhosis • Develop bile duct malignancy Unfortunately, the ideal animal model of PSC does not exist!

  4. Animal Models of Inflammatory Bowel Disease • Toxic injury of the intestinal lining • Genetic models – IL10 genetic deficiency • Immune cell manipulation • Genetic • Adaptive transfer None of these models develop PSC!

  5. What are we doing at Mayo Clinic? • Acute model of PSC in mice • Mdr2-/- chronic models of PSC in mice • Genetic models of bile duct cancer in mice

  6. SMAC MIMETIC ANIMAL MODEL BV6 (0.1 mg/100 L) Saline (100 L) CBD clamp CBD clamp, Gallbladder Injection CBD clamp release sacrifice 45 min Day 5

  7. SM Intra-biliary Injection Results in a PSC-like Phenotype H&E Sirius red αSMA Mac2 Saline M5 BV6 100 µm ALT Alk. Phos Bile Acids Total Bilirubin 14 1400 * * 700 * 250 Saline * 1200 12 600 BV6 200 1000 10 500 units/L 800 units/L 150 8 400 umol/L mg/dL 600 6 300 100 400 4 200 50 200 2 100 0 0 0 0 saline BV6 saline BV6 saline BV6 saline BV6 (N=8) (N=8) * p<0.05

  8. CholangiographicEvidence of Intrahepatic Bile Duct Alterations in Mice Injected with the SM saline BV6

  9. CONCLUSIONS & WORKING MODEL Cholangiocyte apoptosis macrophage cIAPs Fibro-inflammatory cholangiopathy stellate cell cholangiocyte Pro-inflammatory Cytokines & Chemokines

  10. Mdr2 Knock Out Mouse as a Model of PSC • Mdr2-/- • Defect in cannalicular phospholipid transport • PSC-like cholangiopathy in the mouse Obliterative biliary fibrosis • Lazaridis & LaRusso, NEJM 2018 • Lazaridis & LaRusso, Mayo Clin Proc 2016 • Mariotti et al, BiochimBiophys Acta Mol Basis Dis 2018

  11. Reichert MC and Lammert F. Seminars in Liver Disease 2018

  12. Cenicroviroc – CCR2/CCR5 Inhibitor • Oral drug which blocks monocyte/macrophage recruitment to the liver • In clinical trials for PSC NCT02653625 • Completed enrolling (25 patients) • 24 week study

  13. BV6 BV6 + cenicriviroc (CVC) CD68 C57BL/6 mice 5 days after intrabiliary BV6 injection, ± CVC (15 mg/kg, s.c., for 5 days) CVC: CCR2/CCR5 antagonist

  14. Cholangiocyte insult CCR2 CCR2 CCR2 CCL2 CCR2 Monocyte-derived macrophages Circulating monocytes CCR2 inhibition “Cenicriviroc” Bile duct Fibro-inflammatory cholangiopathy

  15. Ductular Reaction • Aberrant reparative response to liver injury1 • Comprise of reactive or activated cholangiocyte-like cells2 • Proliferative • Pro-inflammatory • Pro-fibrotic • Form ductules and extend into liver parenchyma • Progenitor characteristics • Cholangiocyte or hepatocyte derived based on injury model • EpCAM, SOX9, CK7 and CK19, (also markers of cholangiocytes) are used to identify ductular reactive cells in cholestasis • Systemic injection of the cytokine TWEAK induces ductular reaction in normal mice3 • Sato et al, Hepatology 2018 • Banales et al, Nat Rev Gastroenterol Hepatol2019 • Bird et al, PNAS 2013 PanCK SOX9

  16. Question: Does MCL-1 inhibition reduce ductular reaction and fibrosis in vivo? • Serum analysis • Immunohistochemistry • SOX9, PanCK, αSMA • Sirius red, Masson-Trichrome staining S63845 40 mg/kg, IV, 5 days Mdr2-/-

  17. S63845 reduces fibrosis: Mdr2-/- mice S63845 Vehicle Trichrome α-SMA Reduction in fibrosis correlates with attenuated activation of fibroblasts

  18. Animal Models of Cholangiocarcinoma

  19. Summary • Animal models of PSC are important to understand mechanisms of disease and test preclinical therapies • PSC Partners Seeking a Cure has helped support critical research THANKS FOR EVERYTHING YOU DO TO RAISE AWARENESS OF PSC AND SUPPORT RESEARCH RELEVANT TO THIS DISEASE

  20. Acknowledgements Gores lab members Greg Gores Steve Bronk Eugenia Guicciardi Petra Hirsova Tomohiro Katsumi Anuradha Krishnan Ayano Niibe Genome Analysis Core Biomedical Statistics and Informatics Ying Li Optical Microscopy Core

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