Angiogenesis in Viral Immunoinflammatory

Lesions

Barry T. RouseUniversity of Tennessee

Part 4

Does control of angiogenesis represent a smart approach to

control stromal keratitis?

• Problem: many factors to deal with

EMAP IIEndothelial Monocyte Activating Polypeptide

• Cytokine with several effects on neovascularization – Apoptosis of vascular endothelial cells– Upregulates TNF receptors – so TNF

induces apoptosis– Activates tissue factors and blood clots

• Proinflammatory effects• Rationale - targets growing blood

vessels so should inhibit effects of several angiogenic factors

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EMAP II induces apoptosis in vascular endothelial cells in vitro and in vivo

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EMAP II suppresses neovascularization in murine HSK

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EMAP II Suppresses HSK lesion score

Future approaches – possible siRNA targetingtargeting

multiple angiogenesis factors

Preliminary studyPreliminary study

• Plasmid encoding siRNA expressed following Plasmid encoding siRNA expressed following intra-stromal or sub-conjunctival injectionintra-stromal or sub-conjunctival injection

• Mixture of siRNA inhibiting VEGF and VEGF Mixture of siRNA inhibiting VEGF and VEGF receptors gave significant inhibition of receptors gave significant inhibition of

angiogenesis induced by CpGangiogenesis induced by CpG

Inhibition of CpG induced angiogenesis by siRNA delivery

CpG + siLacZ Day 4 CpG + siVEGF, R1, R2 Day 4

General Conclusions

• Herpes induced stromal keratitis an immunoinflammatory lesion

• Neovascularization a major step in pathogenesis

• HSV induces angiogenesis indirectly• Control of angiogenesis inhibits SK• Need multiple approaches for

satisfactory therapy

Colleagues Involved

• Dennis Klinman

• Margaret Schwartz

• Napoleone Ferrara

• Mei Zheng

• Bum-Seok Kim

• Kaustuv Banerjee

• Partha Biswas

• Sujin Lee