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Selective Enhancement of NOD2 Anti-Bacterial Defenses in the Context of Crohn’s Disease

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.

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Selective Enhancement of NOD2 Anti-Bacterial Defenses in the Context of Crohn’s Disease

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  1. 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

  2. DISCLOSURES • Nothing to disclose

  3. Crohn’s is a Multi-Factorial Disease Inappropriate Immune Response to Microbes in a Genetically Susceptible Individual

  4. Current Treatment Options • Anti-Inflammatory • Immune Suppressant • Biologic Therapies • Surgery Do Not Address the Underlying Cause of Disease

  5. NOD LRR CARD 1 28 220 273 577 744 1020 1040 Crohn’s Associated NOD2 Variants X XD R702W G980R L1007fsinsC • 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

  6. Novel Therapeutic Concept P A L A R702W G908R L1007fs NOD2 NOD2 is defective in many CD patients Restoration of NOD2 function will restore health

  7. RIP2 CAD PALA MAPKs NFkB Jnk Erk p38 How Do We Do This? Bacteria (MDP) NOD2 Anti-Bacterial & Pro-Inflammatory Responses Richmond et al., (2012) Gastroenterology

  8. PALA Enhances NOD2 Bacterial Killing Mouse Bone Marrow-Derived Macrophages

  9. Selective Enhancement of NOD2 Function Bacterial Clearance Pro-Inflammatory Cytokine Secretion Human Blood Monocyte-Derived Macrophages

  10. * * -1 -2 -3 0 1 2 3 4 5 6 7 Day: 2.5% DSS PALA: C57BL/6 or NOD2KO male mice 8-10wks old (n=6) Efficacy of CAD Inhibition in Experimental Colitis

  11. 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 • Protectsagainst experimental colitis • Increases function of CD-associated NOD2 variants • May represent a novel approach to CD therapy

  12. 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 Acknowledgements

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