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Crohn Disease : from gene to therapy

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Crohn Disease : from gene to therapy Prof Jean-Pierre Hugot Hopital Robert Debr Paris, France Jean-pierre.hugot_at_rdb.aphp.fr Treatments for Crohn Disease Antibiotics ... – PowerPoint PPT presentation

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Title: Crohn Disease : from gene to therapy


1
Crohn Disease from gene to therapy
  • Prof Jean-Pierre Hugot
  • Hopital Robert Debré
  • Paris, France
  • Jean-pierre.hugot_at_rdb.aphp.fr

2
Gordon Oppenheimer, Burill B Crohn and Leon
Ginzburg, 1969
From  BB Crohn, Life and Work , Falk Foundation
2000
3
Treatments for Crohn Disease
  • Antibiotics
  • Probiotics
  • Nutritional support
  • 5 amino-salicylates
  • Steroids
  • Immunosupressive drugs
  • Antibodies against TNF and other chemiokines
    (IL12, ICAM, a4integrins)
  • Pig parasites

4
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5
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6
Bouma G et al. Nature Rev Immunol 2003
7
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8
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
9
Ibd1-Nod2-Card15
N ter
C ter
NF-kB Activation
Oligomerisation
Bacterial recognition
10
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11
Why to discover genes?
  • To make a diagnosis
  • Before disease occurrence (if prevention
    possible) or to avoid invasive procedures
    (sensibiility, sensitivity).

12
Proportion of mutated patients (all non
conservative variations )
except P268S
13
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)

14
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

15
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

16
Genotype/phenotype relationship response to
Infliximab.
Vermeire S et al. Gastroenterology in press
17
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)

18
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19
From Ogura et al. Nature 2001
20
How a defect in a proinflammatory molecule
..can induce an inflammation?
21
CARD15 -/- mouse
/
-/-
Pauleau AL et al. Mol Cel Biol 2003
22
Interaction between TLR2 and NOD2
Watanabe T Nat Immunol 2004
23
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)

24
Unpublished 
25
CARD15 immunohistochemistry
normal colon
Crohn
Berrebi D et al. Gut 2003
26
Card15 immunohistochemistry
Berrebi D et al. Gut 2003
27
NOD2 and Paneth cells
Crohn normal ileum
Card15
Lysozyme
Ogura Y et al. Gut 2003
28
Screening for Card15/Nod2 interacting small
molecules
  • Loss or gain of function?
  • Which cell line?
  • Role of MDP?

Toward a specific curative thérapy?
29
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)

30
From Rose J et al. Gut 1988
31
ENVIRONMENTAL FACTORS FOR CD
  • 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

32
Commensal flora.
Or specific pathogenic bacteria ?
33
Most popular infectious agents for CD
  • Mycobacterium paratuberculosis
  • E coli,
  • Y enterocolitica
  • L monocytogenes
  • Pseudomonas species

34
way of life
Flora?
Dlg5?
Specific bacteria?
Octn 1/2?
Card15
35
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