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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Billion Years Ago
Atmospheric O2
(%)
Living Cells
Photosynthesis
Plants
Cambrian Explosion
Evolution is intimately linked to atmospheric oxygen
O2 Supply exceeds Demand
O2
HIFα
Adaptive Response to Hypoxia
PHD
Degradation
O2 Demand exceeds Supply
O2
Adaptive Response to Hypoxia
PHDXHIFα
O2 Demand exceeds Supply Increased O2 Supply ( ATP)
Adaptive Response to Hypoxia
PHDXO2
HIFα
Adaptive genes
New Blood VesselsIncreased Vessel Diameter
Increased Blood Oxygenation
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
Hypoxia
PHD
HIF
ADAPTATION
X
BENEFIT?
Hypoxia
PHD
HIF
ADAPTATION
X
BENEFIT?
PHI
Hypoxia and Inflammation
Normal IBD (Ulcerative Colitis)
Overt Pathology of IBD
Diseased Healthy
Diseased + PHI
PHD Inhibition is protective in experimental colitis
PHD Inhibition is protective in experimental colitis
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
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.
•Solubility (core)
•Permeability (core)
•Controlled Release (shell)
Colon Specific Delivery
LEDDS formulation
Sigmoid Pharma
DMOG
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DSS
DSS-IP DMOG
Days
DiseaseActivityIndex
Targeted DMOG delivery
Targeted DMOG delivery
0 1 2 3 4 5 6 70
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4
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8
10
12
DSS
DSS-IP DMOG
DSS + oral DMOG
Days
DiseaseActivityIndex
0 1 2 3 4 5 6 70
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4
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12
DSS
DSS-IP DMOG
DSS + oral DMOG
DSS + oral LEDDS-DMOG
Days
DiseaseActivityIndex
Targeted DMOG delivery
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
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