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Crohn Disease : from gene to therapy

Crohn Disease : from gene to therapy. Prof Jean-Pierre Hugot Hopital Robert Debré Paris, France Jean-pierre.hugot@rdb.aphp.fr. Gordon Oppenheimer, Burill B Crohn and Leon Ginzburg, 1969. From « BB Crohn, Life and Work », Falk Foundation 2000. Antibiotics Probiotics Nutritional support

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Crohn Disease : from gene to therapy

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  1. Crohn Disease : from gene to therapy Prof Jean-Pierre Hugot Hopital Robert Debré Paris, France Jean-pierre.hugot@rdb.aphp.fr

  2. Gordon Oppenheimer, Burill B Crohn and Leon Ginzburg, 1969 From « BB Crohn, Life and Work », Falk Foundation 2000

  3. Antibiotics Probiotics Nutritional support 5 amino-salicylates Steroids Immunosupressive drugs Antibodies against TNF and other chemiokines (IL12, ICAM, a4integrins) Pig parasites Trichuris Suis Treatments for Crohn Disease

  4. Environnemental factor Genetic factor

  5. Bouma G et al. Nature Rev Immunol 2003

  6. IBD loci DLG5 IBD3 IBD7 IBD2 SLC22A4/5 1 2 3 4 5 6 7 8 9 10 11 12 IBD8 IBD6 IBD4 CARD15 13 14 15 16 17 18 19 20 21 22 Y X

  7. NBD TM ? LRR CARD 1 CARD 2 1 121 129 217 270 299 570 744 1020 1040 Ibd1-Nod2-Card15 N ter C ter NF-kB Activation Oligomerisation Bacterial recognition

  8. Why to discover genes? • To make a diagnosis • Before disease occurrence (if prevention possible) or to avoid invasive procedures (sensibiility, sensitivity).

  9. Proportion of mutated patients (all non conservative variations *) *except P268S

  10. Why to discover genes? • To make a diagnosis • Before disease occurrence (if prevention possible) or to avoid invasive procedures (sensibiility, sensitivity). • To classify the disease (definition of disease subgoups)

  11. NOD2/CARD15 mutations are associated with : • A younger age of onset • A more frequent ileal involvement • An higher complication rate • Lesage et al. Am J Hum Genet 2002 • Vermeire et al. Am J Hum Genet 2002 • Cuthbert et al. Gastroenterology 2002 • Hampe et al. Lancet 2002 • Amhad et al. Gastroenterology 2002 • Abreu et al. Gastroenterology 2002 • Louis E et al. Gut 2003

  12. Why to discover genes? • To make a diagnosis • Before disease occurrence (if prevention possible) or to avoid invasive procedures (sensibiility, sensitivity). • To classify the disease (definition of disease subgoups) • To develop a treatment • Gene therapy (in the future?) • Pharmacogenetics

  13. Genotype/phenotype relationship : response to Infliximab. Vermeire S et al. Gastroenterology in press

  14. Why to discover genes? • To make a diagnosis • Before disease occurrence (if prevention possible) or to avoid invasive procedures (sensibiility, sensitivity). • To classify the disease (definition of disease subgoups) • To develop a treatment • Gene therapy (in the future?) • Pharmacogenetics • Drug discovery (disease mechanisms)

  15. From Elson C. N Eng J Med 2002

  16. From Ogura et al. Nature 2001

  17. How a defect in a proinflammatory molecule… ..can induce an inflammation?

  18. CARD15 -/- mouse +/+ -/- Pauleau AL et al. Mol Cel Biol 2003

  19. Interaction between TLR2 and NOD2 Watanabe T Nat Immunol 2004

  20. How CD mutations induce the inflammation? • A defect in the innate immunity induces an excess of response by the adaptive immunity which is deleterious for the mucosa. • CD mutations are gain of fonction mutations (Maeda S Science 2005) • CD mutations do not inhibit pro-inflammatoy pathways (Watanabe T Nature Immunol 2004; Chen CM J Biol Chem 2004) • CD mutations no more activate anti-inflammatory pathways (IL10) (Netea MG Eur J Immunol 2004)

  21. Unpublished 

  22. CARD15 immunohistochemistry normal colon Crohn Berrebi D et al. Gut 2003

  23. Card15 immunohistochemistry Berrebi D et al. Gut 2003

  24. NOD2 and Paneth cells Crohn normal ileum Card15 Lysozyme Ogura Y et al. Gut 2003

  25. Screening for Card15/Nod2 interacting small molecules • Loss or gain of function? • Which cell line? • Role of MDP? Toward a specific curative thérapy?

  26. Why to discover genes? • To make a diagnosis • Before disease occurrence (if prevention possible) or to avoid invasive procedures (sensibiility, sensitivity). • To classify the disease (definition of disease subgoups) • To develop a treatment • Gene therapy (in the future?) • Pharmacogenetics • Drug discovery (disease mechanisms) • Prevention (environmental factors)

  27. From Rose J et al. Gut 1988

  28. Tobacco Refined sugars Fast-food and Cola Microparticles Tooth paste Chewing-Gum Margarin Fibres Backer yeast Alcohol Caffe Corn-flakes Curry Hot water Refrigeration Perinatal Infections Infections in childhood Antibiotics Adenoïdectomy Breast feeding Life events Oral contraceptives ENVIRONMENTAL FACTORS FOR CD

  29. Commensal flora…. Or specific pathogenic bacteria ?

  30. Mycobacterium paratuberculosis E coli, Y enterocolitica L monocytogenes Pseudomonas species Most popular infectious agents for CD

  31. way of life Flora? Dlg5? Specific bacteria? Octn 1/2? Card15

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