1. Punching Above its Weight: Asthma Research in Canada Paul M O’Byrne EJ Moran Campbell Professor of Medicine Firestone Institute for Respiratory Health, St. Joseph’s Healthcare and McMaster University, Hamilton, Ontario, Canada

2. Potential for Conflict of Interest Advisory Boards: Acetelion, AstraZeneca, GlaxoSmithKline, Merck, Resistentia, Topigen. Speakers Fees: AstraZeneca, Chiesi, GlaxoSmithKline. Grants-in-Aid: Alexion, AstraZeneca, Genentech, GlaxoSmithKline, Medimmune, Merck, Schering Plough, Wyeth.

3. Manny Pacquiao Filipino professional boxer an eight division world champion the first boxer in history to win ten world titles the first to win in eight weight divisions named "Fighter of the Decade" for the 2000's

4. 9, 984,670 sg Km 6.7% total land mass Canada Population 34M 0.6% world’s population 17 Medical Schools 133 in USA 33 in UK 22 in Australia/NZ Since 1980: Asthma 96K publications 5.5K Canadian 5.7% total 18 of 100 most cited asthma papers include Canadian investigators

5. Pulmonary Citations 1998-2009 Lab Times 2011; 2:42-44 Canada: Third in the world for pulmonary citations, behind USA and UK; but with a higher citation/article rate than either

6. Most Cited Asthma Publications from Canadian Investigators

7. Canadian Centers of Excellence Montreal Quebec City Toronto Hamilton Winnipeg Saskatoon Edmonton Calgary Vancouver

8. Game Changers: Asthma Diagnosis and Treatment

9. Fellows Trained in Hamilton

10. Canadian Consensus Guidelines Juniper E, 1990 OPTIMA A 2001 START 2003 FACET 1997 OPTIMA B 2001 Boulet, 1997 Cox G, 2007 Nair P, 2009

11. 11 Bronchial Thermoplasty Catheter has an expandable wire array at the tip Radiofrequency energy that is converted to heat in the airway wall Monopolar radiofrequency (RF) energy  Temperature controlled: 65 °C  10 seconds  Signal for successful activation Multiple safety algorithms to ensure controlled energy delivery

12. Bronchial Thermoplasty Cox PG, et al. New Engl J Med 2007; 356:1327-37.

13. Bronchial Thermoplasty Cox PG, et al. New Engl J Med 2007; 356:1327-37.

14. Induced Sputum O’Byrne PM, Nair P. Lancet 2006; 368:794-308

15. Asthma Exacerbations Nair P, et al. N Engl J Med 2009; 360:985-93.

16. NCE Clinical Investigator Collaborative PM O’Byrne GM Gauvreau L-P Boulet JM Fitzgerald DW Cockcroft I Mayers R Leigh

17. New Drugs for Asthma Modifications of existing drugs: –Untra-longacting inhaled β 2 -agonists –Modified inhaled corticosteroids –Glucocorticosteroid receptor agonists –New ICS/LABA combinations New approaches –Anti-sense against IL-3, IL-3, GM-CSF and CCR –Anti-sense IL-4R –Anti-IL-9 –Anti-IL-13 –Anti-C5 a –Anti-Ox 40L –CXCR2 antagonist

18. ALLERGIC ASTHMA

21. GAUVREAU GM,et al. Am J Resp Crit Care Med 1999: 160; 640-7 DiluentAllergen Baseline 7h % Fall in FEV 1 * * * * * * * * * * *

22. Transcription Nucleus DNA (GENE) RNA 1. Antisense (ssDNA) RNAseH 2. siRNA (dsRNA) RISC Promoter 4. Decoy (dsDNA) Transcription factor 5. Aptamer (DNA or RNA) Translation 3. ISS/ CpG motif (ssDNA) TLR9 Immuno- stimulation mRNA degradation PROTEIN “Blocks” receptor function! Competition for TF “Blocks” transcription! Oligonucleotide Therapeutic Approaches RNAseH Paolo Renzi MD.

23. Rationale: By down-regulating the expression of the eotaxin receptor (CCR3) and the common beta chain for IL-3, IL-5, and GM-CSF, –an inhaled anti-sense, ASM8 will inhibit the migration and survival of eosinophils, basophils, mast cells. –and thereby inhibit allergen-induced airway responses.

24. Effect of ASM8 on βc and CCR-3 mRNA in sputum cells % change from pre-allergen levels Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.

25. Sputum Cell Counts Pre-dose vs Post Allergen Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.

26. Allergen-Induced Sputum Eosinophilia p=0.005 p=0.043

27. Allergen-induced Fall in FEV1 EAR LAR

28. IL-4 and IL-13 Kasaian M, Miller D. Biochem Pharm 2008; 76:147-55

29. IL-13 in Asthmatic Sputum Berry MA, et al. J Allergy Clin Immunol 2008; 121:685-91 Berry MA, et al. J Allergy Clin Immunol 2004; 114:1106-9

30. IL-4 Mutene on Allergen-Induced Responses Wenzel S, et al. Lancet 2007; 370:1422-31

31. Anti-IL-13 Test product, dose, and mode of administration: IMA-638 hMab, humanized IgG1  2x2 mg/kg, subcutaneous Duration of treatment: 2 doses 7 days apart Reference therapy: placebo: SC formulation excipients only

32. Effect on Allergen-Induced Airway Responses Gauvreau GM, et al. Am J Respir Crit Care Med 2011; 183:1007-14.

33. Effect on Allergen-Induced Airway Hyperresponsiveness Gauvreau GM, et al. Am J Respir Crit Care Med 2011; 183:1007-14.

34. Effect on Allergen-Induced Sputum Eosinophilia Gauvreau GM, et al. Am J Respir Crit Care Med 2011; 183:1007-14.

35. The C anadian H ealthy I nfant L ongitudinal D evelopment (CHILD) study - a collaborative study of the effects of environment on children’s health

38. CHILD – a 5-year study of 5,000 children In-utero- recruitment: maternal, paternal and sibling studies; clinical, stress and environment questionnaires Delivery- delivery: outcomes, cord blood, meconium, urine 3 months- home visit: inspection, dust sampling, breast-milk - infant lung function, stress (sub-cohorts), infections 6 months- telephone questionnaire follow-up 1 year- clinic: skin tests, blood, nasal, lung function, infections 1 ½ years- telephone questionnaire follow-up 2 years- telephone questionnaire follow-up 2 ½ years- telephone questionnaire follow-up 3 years- clinic: questionnaires, skin tests, lung function, blood 4 years- telephone questionnaire follow-up 5 years- clinic: questionnaires, clinical assessment, skin tests, lung function, blood, physician assessment

39. C anadian H ealthy I nfant L ongitudinal D evelopment (CHILD) investigators Allan Becker Dean Befus Michael Brauer Jeff Brook Edith Chen Michael Cyr Denise Daley Sharon Dell Judah Denburg Susan Elliott Hartmut Grasemann Kent HayGlass Rick Hegele Linn Holness Michael Kobor Tobias Kollman Tulay Koru-Sengul A nita Kozyrksyj Catherine Laprise Wendy Lou Piush Mandhane Greg Miller Redwan Moqbel Peter Pare Clare Ramsey Felix Ratjen Andy Sandford James Scott Jeremy Scott Malcolm Sears Fran Silverman PJ Subbarao Tim Takaro Scott Tebbutt Teresa To Stuart Turvey

40. Disciplines involved in developing the Canadian Healthy Infant Longitudinal Development study Epidemiology Neonatology Pediatrics Population health Environmental assessment Environmental hygiene Nutrition Infectious disease Genetics Obstetrics Geographic Information Systems Endocrinology/metabolism Mind-body Physiology Immunology Allergy Air quality Toxicology Sociology Molecular biology Psychology Neuroimmunology Biostatistics Ethics and legal Respirology Occupational health

41. Recruitment Sites for CHILD Study

42. Summary Canadian respiratory research is among the strongest in the world. Asthma research is a particular strength. This success is achieved in spite of the fact that funding for respiratory research is likely the worst for developed countries. Asthma research community is the most collegial in the world!!