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Benefits of Targeting SCF/c-KIT in ophthalmology (in comparison of VEGF)

1Inhibition of Compensatory Pathway for Angiogenesis and Vascular Leakage

The most valuable finding of our research team was that SCF/c-KIT increase vascular permeability and drives angiogenesis without the involvement of VEGF. SCF and VEGF share most of the downstream signal pathway, but SCF does not phosphorylate KDR(VEGFR-2) and VEGF does not phosphorylate c-KIT. Understandably, vascular leakage and neovascularization induced by SCF/c-KIT are not mediated by inhibition of VEGF signal, making SCF/c-KIT a valuable ophthalmology drug target, especially for anti-VEGF refractory patients.

2Enhanced Safety, especially in a Longer Term

Since the introduction of anti-VEGF drugs, FDA and EMA have raised concerns of inhibiting VEGF, such as thromboembolic events and cardiovascular risk. These concerns are based on that VEGF signaling is required for vascular homeostasis.

Unlike VEGF, SCF/c-KIT engages in angiogenesis only under the pathogenic condition, and we verified in knock-out mice that blocking the SCF/c-KIT signal has no harm to the normal functioning of endothelial cells. This finding could be a meaningful difference when considering that retinal diseases caused by aberrant neovascularization require a lifetime drug intervention under current treatment regimen, just like chronic diseases.

3Resolution of Hypoxia, a Root Cause of Angiogenesis

Vascular dysfunction due to vessel occlusion or rupture is a pathogenic driver in retinopathy. It causes a deficiency in the amount of oxygen to the tissues; a phenomenon called hypoxia.

Hypoxia upregulates HIF-1a (Hypoxia-inducible factor 1-alpha) and induces expression of SCF/c-KIT, along with VEGF/VEGFR, and other angiogenic factors. The activation of SCF/c-KIT signaling promotes the expression of VEGF and VEGFR, and stabilizes nuclear HIF-1a in turn, leading to the formation of a positive feedback loop for amplification of hypoxia-mediated neovascularization. The synergy of hypoxia and activated SCF/c-KIT signal repeatedly exacerbates the pathogenic environment by inducing abnormal neovascularization in the retina. Therefore, the inhibition of SCF/c-KIT signaling could break a vicious circle of hypoxia and angiogenesis, which is an effective treatment for retinal diseases.

4Normalization of Avascular Area

Along with tufts resulting from neovascularization, avascular areas in the retina which are devoid of normal vasculature contributes to blindness. To effectively treat ocular diseases, it is essential to both remove vascular tufts and normalize avascular retina. However, according to a paper(Clayton C. Tokunaga et al., IOVS, 2014), aflibercept increases the area of avascular retina in OIR model mice in a dose-dependent manner.

On the other hand, we have confirmed in OIR model mice that both neovascularization and avascular areas have been repeatedly reduced in c-KIT knock-out mice and by the treatment of anti-SCF antibody, compared with wild type mice. This result implies that anti-SCF/c-KIT could break the efficacy ceiling of anti-VEGF drugs, which is merely maintaining vision loss of fewer than 15 letters in BCVA during clinical trials.