Selective Enhancement of
NOD2 Anti-Bacterial Defenses
in the Context of
Crohn’s Disease
Christine McDonald, PhD
Department of Pathobiology
Lerner Research Institute
Cleveland Clinic
DISCLOSURES
• Nothing to disclose
Crohn’s is a Multi-Factorial Disease
Inappropriate Immune Response to Microbes
in a Genetically Susceptible Individual
Current Treatment Options
»Anti-Inflammatory
»Immune Suppressant
»Biologic Therapies
»Surgery
Do Not Address the Underlying Cause of
Disease
NOD
CARD
1 28
220 273
LRR
577
X744
X D
1020 1040
R702W G980R L1007fsinsC
Crohn’s Associated NOD2 Variants
• 3 major variants found in or near LRRs
• Disease prevalence:
–1 variant: 30-50% prevalence, 2-4x increased risk
–2 variants: 10% carry, ~17-40x increased risk
• Associated with early & aggressive disease
• Variants result in loss of NOD2 function
Novel Therapeutic Concept
P
R702W
A
G908R
L
L1007fs
A
NOD2
NOD2 is defective in many CD patients
Restoration of NOD2 function will restore health
How Do We Do This?
Bacteria
(MDP)
NOD2
PALA
CAD
RIP2
MAPKs
NFkB
Jnk
p38
Anti-Bacterial
&
Pro-Inflammatory
Responses
Richmond et al., (2012) Gastroenterology
Erk
PALA Enhances NOD2 Bacterial Killing
Mouse Bone Marrow-Derived Macrophages
Pro-Inflammatory Cytokine Secretion
Bacterial Clearance
Selective Enhancement of NOD2 Function
Human Blood Monocyte-Derived Macrophages
Efficacy of CAD Inhibition in
Experimental Colitis
Day: -1
-2
-3
0
1
2
*
3
4
5
6
*
7
2.5% DSS
PALA:
C57BL/6 or NOD2KO male mice 8-10wks old (n=6)
Summary
• Decreased NOD2 function is linked to CD
• CAD is a negative regulator of NOD2
• CAD inhibitor treatment:
– Enhances bactericidal NOD2 functions without
increasing inflammation
– Protects against experimental colitis
– Increases function of CD-associated NOD2
variants
– May represent a novel approach to CD therapy
Acknowledgements
Cleveland Clinic
• McDonald Lab
– Chaorui Tian
– Amrita Kabi
– Craig Homer
– Kourtney Nickerson
– Laura Dixon
– Amy Richmond
• IBD Research Group
– JP Achkar
• Keyonna Smith
– Claudio Fiocchi
– Carol de la Motte
• Sean Kessler
– Eleni Stylianou
– Michelle Longworth
• Imaging & Histology Core
University of Michigan
• Gabriel Nuñez
• Arul Chinnaiyan
• Alexey Nesvizhskii
• Arun Sreekumar
Funding Support
• DoD PRMRP - PR110887
• CCFA Career Development Award
• NIDDK R01 - DK082437
• NIDDK T32 Training Grant
• LRI Chairman’s Innovative
Research Award
• Gerald & Nancy Goldberg
Resources
• George Stark (CCF)
• Laura Lindsey-Boltz (UNC)
• NCI / DTP Open Chemical Repository
• NCI Cooperative Human Tissue Network
• CCF/CWRU CTSC