Prof. Cormac Taylor, UCD Conway Institute
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Targeting oxygen-sensitive pathways in Inflammatory Bowel Disease.
Cormac Taylor, PhDUCD Conway Institute
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0
5
10
15
20
25
4.5 3.5 2.5 1.5 0.5
Billion Years Ago
Atmospheric O2
(%)
Living Cells
Photosynthesis
Plants
Cambrian Explosion
Evolution is intimately linked to atmospheric oxygen
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O2 Supply exceeds Demand
O2
HIFα
Adaptive Response to Hypoxia
PHD
Degradation
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O2 Demand exceeds Supply
O2
Adaptive Response to Hypoxia
PHDXHIFα
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O2 Demand exceeds Supply Increased O2 Supply ( ATP)
Adaptive Response to Hypoxia
PHDXO2
HIFα
Adaptive genes
New Blood VesselsIncreased Vessel Diameter
Increased Blood Oxygenation
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Adaptive genes
New Blood VesselsIncreased Vessel Diameter
Increased Blood Oxygenation
Increased O2 Supply ( ATP)
Adaptive Response to Hypoxia
O2 Supply exceeds Demand
O2
PHD
Degradation
HIFα
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Hypoxia
PHD
HIF
ADAPTATION
X
BENEFIT?
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Hypoxia
PHD
HIF
ADAPTATION
X
BENEFIT?
PHI
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Hypoxia and Inflammation
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Normal IBD (Ulcerative Colitis)
Overt Pathology of IBD
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Diseased Healthy
Diseased + PHI
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PHD Inhibition is protective in experimental colitis
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PHD Inhibition is protective in experimental colitis
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Model Inhibitor Reference
FG4497
DMOG
TNBS Colitis Robinson et al. Gastroenterology, 2008
Hindryckx et al. Inflamm. Bowel Disease, 2010DSS Colitis
TNF-DARE Ileitis Hindryckx et al. J Immunol, 2010
Hirota, et al., Gastroenterology 2010C. Dificile toxin
Ischemia-Reperfusion Hart et al., J. Immunol 2011
DMOG
DMOG
DMOGMarchbank et al., Lab Invest 2011DMOGIndomethacin
PHD Inhibition is protective in experimental colitis
PHD1KO Tambuwala et al. Gastroenterology, 2010DSS Colitis
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Possible Side Effects of Systemic PHI administration.
-Unwanted erythropoesis.
-Unwanted angiogenesis.
…..it would be beneficial to develop a formulation of PHI which could be targeted to regions of inflammation.
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•Solubility (core)
•Permeability (core)
•Controlled Release (shell)
Colon Specific Delivery
LEDDS formulation
Sigmoid Pharma
DMOG
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0 1 2 3 4 5 6 70
2
4
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8
10
12
DSS
DSS-IP DMOG
Days
DiseaseActivityIndex
Targeted DMOG delivery
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Targeted DMOG delivery
0 1 2 3 4 5 6 70
2
4
6
8
10
12
DSS
DSS-IP DMOG
DSS + oral DMOG
Days
DiseaseActivityIndex
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0 1 2 3 4 5 6 70
2
4
6
8
10
12
DSS
DSS-IP DMOG
DSS + oral DMOG
DSS + oral LEDDS-DMOG
Days
DiseaseActivityIndex
Targeted DMOG delivery
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Acknowledgements
The Conway Institute
Kathryn Oliver
Eoin Cummins
Murtaza Tambuwala
Trinity College DublinPadraic Fallon
Carsten ScholzUlrike Bruning-Rossow
Bettina SchaibleColin LenihanJohn Garvey
Terence Agbor
Sigmoid Pharma
IRCSET
Ivan Coulter