Post on 15-Jan-2016
Punching Above its Weight:Asthma Research in Canada
Paul M O’ByrneEJ Moran Campbell Professor of Medicine
Firestone Institute for Respiratory Health,
St. Joseph’s Healthcare and McMaster University,
Hamilton, Ontario, Canada
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.
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
9, 984,670 sg Km6.7% total land mass
Canada
Population 34M0.6% world’s population
17 Medical Schools133 in USA33 in UK22 in Australia/NZ
Since 1980: Asthma96K publications5.5K Canadian5.7% total
18 of 100 most cited asthma papers includeCanadian investigators
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
Most Cited Asthma Publications from Canadian Investigators
Canadian Centers of Excellence
Montreal
Quebec City
Toronto
Hamilton
Winnipeg
Saskatoon
Edmonton
Calgary
Vancouver
Game Changers: Asthma Diagnosis and Treatment
Canadian Consensus Guidelines
Juniper E, 1990OPTIMA A 2001
START 2003
FACET 1997OPTIMA B 2001
Boulet, 1997Cox G, 2007 Nair P, 2009
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
Bronchial Thermoplasty
Cox PG, et al. New Engl J Med 2007; 356:1327-37.
Bronchial Thermoplasty
Cox PG, et al. New Engl J Med 2007; 356:1327-37.
Induced Sputum
O’Byrne PM, Nair P. Lancet 2006; 368:794-308
Asthma Exacerbations
Nair P, et al. N Engl J Med 2009; 360:985-93.
NCE Clinical Investigator Collaborative
PM O’Byrne
GM Gauvreau
L-P Boulet
JM Fitzgerald
DW Cockcroft
I Mayers R Leigh
New Drugs for Asthma
• Modifications of existing drugs:– Untra-longacting inhaled β2-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-C5a
– Anti-Ox 40L– CXCR2 antagonist
Goblet cell hyperplasia, mucus production &
epithelial desquamationAltered neural
mediators
Increasedsmooth muscle
&altered function
Edema and lossof airway
tethering to parenchyma
Myofibroblasthyperplasia &
fibrosis
Dendritic cell, lymphocyte & mast cell
mediated events
Inflammatory cell production,recruitment andmediator release
Initial antigen recognition, T-cell orientation
and IgE production
AHRALLERGICASTHMA
FEV1
(L)
FEV1
(L)
Time Post-Inhalation (h)
0 1 2 3 4 5 6 7 8
3.0
3.5
4.0
4.5
5.0
3.0
3.5
4.0
4.5
5.0
Grass Pollen
House Dust Mite
CARTIER A , et al. J Allergy Clin Immunol 1982; 70:170-7
16
8
4
2
1
0.5
4
2
1
0.5
Days after Allergen Inhalation
0 1 2 3 4 5 6 7 8 9 17 19 45 73 129
Ratio Change
in Histamine
PC20
+2
0 SD
-2
+2
0 SD
-2
24h 2d 4d 7dTime Post Inhalation
0
5
10
15
20
SputumMCC
(x10 4 /ml)
0
100
200
300
SputumEosinophils
(x10 4 /ml)
24h 2d 4d 7d.5
1
2
4
8
MCh PC 20
(mg/ml)
-30
-20
-10
0
.5
1
2
4
8
GAUVREAU GM, et al. Am J Resp Crit Care Med 1999: 160; 640-7
Diluent Allergen
Baseline
Baseline
7h
7h
% Fall in FEV1
*
**
**
*
* * * **
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
mRNAdegradation
PROTEIN
“Blocks”receptorfunction!
Competition for TF“Blocks” transcription!
Oligonucleotide Therapeutic Approaches
RNAseH
Paolo Renzi MD.
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.
Effect of ASM8 on βc and CCR-3 mRNA in sputum cells
% c
han
ge
fro
m p
re-a
llerg
en le
vels
% c
han
ge
fro
m p
re-a
llerg
en le
vels
Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.
SPUTUM TOTAL CELLS COUNTPRE-DOSE (DAY 1) & 7 HRS POST-ALLERGEN (DAY 3)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0 PLACEBO
ASM8
PRE POST PRE POST
TO
TA
L C
EL
LS
CO
UN
T (
X1
06 C
EL
LS
)(M
ea
n +
/-
SE
M)
SPUTUM EOSINOPHILS CELL COUNTPRE-DOSE (DAY 1) & 7 HRS POST-ALLERGEN (DAY 3)
0.00
0.25
0.50
0.75
1.00
1.25
1.50 PLACEBO
ASM8
PRE POST PRE POST
* * p= 0.0059 (Placebo vs ASM8)
**
EO
SIN
OP
HIL
S C
EL
L C
OU
NT
(X
10
6 CE
LL
S)
(Me
an
+/-
S
EM
)
Sputum Cell CountsPre-dose vs Post Allergen
Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.
Allergen-Induced Sputum Eosinophilia
pre 7h 24h0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
Baseline
8 mg OD
1 mg BID2 mg BID4 mg BID
Time Post Allergen Challenge
Sp
utu
m E
osi
no
ph
ils
(X 1
06 c
ells
)
screen 1 mg BID 2 mg BID 4 mg BID 8 mg OD0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
Dose Level
Sp
utu
m E
osi
no
ph
ils
(X 1
06)
7 h
post
allerg
en
screen 1 mg BID 2 mg BID 4 mg BID 8 mg OD0.0
0.2
0.4
0.6
0.8
1.0
1.2
Dose Level
Sp
utu
m E
osi
no
ph
ils
(X 1
06)
24 h
po
st a
ller
gen
p=0.005
p=0.043
Allergen-induced Fall in FEV1
0 1 2 3 4 5 6 7
-5
0
5
10
15
20
25
30
35
40
Baseline 4 mg BID 8 mg OD1 mg BID 2 mg BID
Time (h)
Fal
l in
FE
V1 (
%)
EAR LAR
IL-4 and IL-13
Kasaian M, Miller D. Biochem Pharm 2008; 76:147-55
IL-13 in Asthmatic Sputum
Berry MA, et al. J Allergy Clin Immunol 2008; 121:685-91Berry MA, et al. J Allergy Clin Immunol 2004; 114:1106-9
IL-4 Mutene on Allergen-Induced Responses
Wenzel S, et al. Lancet 2007; 370:1422-31
Anti-IL-13
• Test product, dose, and mode of administration: IMA-638 hMab, humanized IgG12x2 mg/kg, subcutaneous
• Duration of treatment: 2 doses 7 days apart
• Reference therapy: placebo: SC formulation excipients only
Effect on Allergen-Induced Airway Responses
Gauvreau GM, et al. Am J Respir Crit Care Med 2011; 183:1007-14.
Effect on Allergen-Induced Airway Hyperresponsiveness
Gauvreau GM, et al. Am J Respir Crit Care Med 2011; 183:1007-14.
Effect on Allergen-Induced Sputum Eosinophilia
Gauvreau GM, et al. Am J Respir Crit Care Med 2011; 183:1007-14.
The Canadian Healthy Infant
Longitudinal Development
(CHILD) study
- a collaborative study of the effects of environment on
children’s health
CHILD – a 5-year study of 5,000 childrenIn-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
Canadian Healthy Infant Longitudinal
Development (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
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
Recruitment Sites for CHILD Study
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!!