Selective Enhancement ofNOD2 Anti-Bacterial Defenses

in the Context ofCrohn’s Disease

Christine McDonald, PhDDepartment of Pathobiology

Lerner Research InstituteCleveland Clinic

DISCLOSURES

• Nothing to disclose

Crohn’s is a Multi-Factorial Disease

Inappropriate Immune Response to Microbesin a Genetically Susceptible Individual

Current Treatment Options

»Anti-Inflammatory»Immune Suppressant»Biologic Therapies»Surgery

Do Not Address the Underlying Cause of Disease

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

1 28 220 273 577 744 10401020

CARD NOD LRR

X X

R702W G980R L1007fsinsC

PALA

Novel Therapeutic Concept

NOD2 is defective in many CD patients

Restoration of NOD2 function will restore health

R702WG908R

L1007fs

NOD2

How Do We Do This?Bacteria (MDP)

NFB

RIP2

NOD2

ErkJnkp38

MAPKs

CADPALA

Anti-Bacterial&

Pro-InflammatoryResponses

Richmond et al., (2012) Gastroenterology

PALA Enhances NOD2 Bacterial Killing

Mouse Bone Marrow-Derived Macrophages

Selective Enhancement of NOD2 FunctionBa

cter

ial C

lear

ance

Pro-Inflamm

atory Cytokine Secretion

Human Blood Monocyte-Derived Macrophages

Efficacy of CAD Inhibition inExperimental Colitis

2.5% DSS-1 -2 0-3 1 2 3 4 5 6 7Day:

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

AcknowledgementsCleveland 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