Targeting oxygen-sensitive pathways in Inflammatory Bowel Disease.

Cormac Taylor, PhDUCD Conway Institute

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

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

0 1 2 3 4 5 6 70

2

4

6

8

10

12

DSS

DSS-IP DMOG

Days

DiseaseActivityIndex

Targeted DMOG delivery

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

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

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