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G. Cotugno, E. M. Surace, P. Colella, A. Auricchio; Novel Strategies to Inhibit Ocular Neovascularization Based on Sonic Hedgehog Pathway Blockade. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3409.
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Ocular neovascularization is the major landmark of several common retinal and choroidal blinding diseases including proliferative diabetic retinopathy and age-related macular degeneration, for which no effective therapy is currently available. Recently we have observed that the Sonic Hedgehog (Shh) pathway is activated in animal models of retinal and choroidal neovascularization and that its pharmacological inhibition results in significant reduction of neovascularization in both models, suggesting this pathway as a new molecular target for treatment of ocular neovascular diseases. We are currently developing two novel strategies to inhibit the Shh pathway in the retina.Methods and
The Hedgehog Interacting Protein (HIP) is a membrane glycoprotein able to bind and sequester Shh thus inhibiting its pathway; we have generated a soluble decoy form of the Hip protein lacking its transmembrane domain (HIP-Δ-22) which may be used to block Shh extracellular diffusion, preventing its binding to the Patched receptor. We have demonstrated that recombinant HIP-Δ-22, secreted in the medium of transfected 293 cells, is able to bind Shh. In addition we have generated type 1 adeno-associated viral vectors (AAV1) expressing HIP-Δ-22 and we have administered them to the retina of a murine model of retinal neovascularization, the retinopathy of prematurity (ROP) mice. This resulted in the reduction of pathological vessel formation, suggesting the ability of the HIP-Δ-22 decoy receptor to block the Shh pathway in this model. The second approach we are testing to inhibit Shh is based on short interfering RNAs (siRNA) able to silence Shh expression. We have designed five different siRNA oligos complementary to regions of identity between human and murine Shh mRNA. Two oligos resulting in >70% reduction of Shh expression in 293 trasfected cells have been selected. Periocular injections of the two selected oligos resulted in reduction of Shh expression in the retina of C57Bl6 mice. Experiments aimed at inhibiting ocular neovascularization in ROP mice are in progress.
Our results support the involvement of the Shh pathway in the development of ocular neovascularization and suggest novel potential therapeutic strategies for treatment of ocular neovascular diseases.
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