Transcript Crohn Disease : from genes to therapy

Crohn Disease :
from gene to therapy
Prof Jean-Pierre Hugot
Hopital Robert Debré
Paris, France
[email protected]
Gordon Oppenheimer, Burill B Crohn and Leon Ginzburg, 1969
From « BB Crohn, Life and Work », Falk Foundation 2000
Treatments for Crohn Disease
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Antibiotics
Probiotics
Nutritional support
5 amino-salicylates
Steroids
• Immunosupressive drugs
• Antibodies against TNF
and other chemiokines
(IL12, ICAM, a4integrins)
• Pig parasites
Trichuris Suis
Environnemental factor
Genetic factor
Bouma G et al. Nature Rev Immunol 2003
IBD loci
IBD7
1
DLG5
IBD3
SLC22A4/5
2
3
4
5
6
IBD8
IBD4
IBD2
7
8
9
10
11
12
20
21
22
Y
X
IBD6
CARD15
13
14
15
16
17
18
19
Ibd1-Nod2-Card15
N ter
CARD 1 CARD 2
1
121 129 217 270 299
NF-kB
Activation
C ter
NBD
TM ?
570
Oligomerisation
744
LRR
1020 1040
Bacterial recognition
Why to discover genes?
• To make a diagnosis
• Before disease occurrence (if prevention
possible) or to avoid invasive procedures
(sensibiility, sensitivity).
Proportion of mutated patients
(all non conservative variations *)
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
2 mutations
1 mutation
0 mutation
CD (n=453)
UC (n=159)
controls (n=103)
*except P268S
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)
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
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Hampe et al. Lancet 2002
Amhad et al. Gastroenterology 2002
Abreu et al. Gastroenterology 2002
Louis E et al. Gut 2003
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
Genotype/phenotype relationship :
response to Infliximab.
60
50
wild type
40
% 30
heterozygous
20
10
0
Complete
Response
(n=132)
Partial
response
(n=58)
No Response
(n=55)
homozygous and
compound
heterozygous
Vermeire S et al. Gastroenterology in press
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)
From Elson C.
N Eng J Med 2002
From Ogura et al. Nature 2001
How a defect in a
proinflammatory molecule…
..can induce an inflammation?
CARD15 -/- mouse
+/+
-/-
Pauleau AL et al. Mol Cel Biol 2003
Interaction between TLR2 and NOD2
Watanabe T Nat Immunol 2004
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)
Unpublished
CARD15 immunohistochemistry
normal colon
Crohn
Berrebi D et al. Gut 2003
Card15 immunohistochemistry
Berrebi D et al. Gut 2003
NOD2 and Paneth cells
Crohn normal ileum
Card15
Lysozyme
Ogura Y et al. Gut 2003
Screening for Card15/Nod2 interacting
small molecules
• Loss or gain of function?
• Which cell line?
• Role of MDP?
Toward a specific curative thérapy?
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)
From Rose J et al. Gut 1988
ENVIRONMENTAL FACTORS FOR CD
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Tobacco
Refined sugars
Fast-food and Cola
Microparticles
Tooth paste
Chewing-Gum
Margarin
Fibres
Backer yeast
Alcohol
Caffe
Corn-flakes
Curry
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Hot water
Refrigeration
Perinatal Infections
Infections in childhood
Antibiotics
Adenoïdectomy
Breast feeding
Life events
Oral contraceptives
Commensal flora….
Or specific pathogenic bacteria ?
Most popular infectious agents for CD
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Mycobacterium paratuberculosis
E coli,
Y enterocolitica
L monocytogenes
Pseudomonas species
way of life
Flora?
Dlg5?
Octn 1/2?
Specific
bacteria?
Card15