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Combined cell and gene therapy towards the treatment of age-related macular degeneration and diabetic retinopathy

      Abnormal and leaky blood vessel growth (neovascularization, NV), caused by an up-regulation of VEGF, is the common cause for vascular leakage, vessel dilatation, tortuosity, haemorrhage, cell death and ultimately blindness in age-related macular degeneration and diabetic retinopathy. Current anti-VEGF treatments (e.g. Avastin) can improve visual function but only temporarily and therefore patients require monthly eye injections. In addition, the anti-VEGF therapies cause side effects such as stroke, gastrointestinal perforations and bleeding. To address these problems, we have generated a novel bi-functional VEGF trap (VEGF Sticky-trap) that is able to trap VEGF as well as bind (“stick”) to the extracellular matrix (ECM). This consequently allows inhibition of neovascularization only at the site of administration without causing systemic side effects as we have demonstrated in a retinopathy mouse model (OIR). To avoid the invasiveness of current therapies we have genetically engineered human embryonic cells that express VEGF Sticky-trap in an inducible manner and further differentiated the cells to retinal pigment epithelium. We have shown that VEGF Sticky-trap expressed by these cells in-vitro is able to bind to ECM and trap soluble VEGF only upon doxycycline induction. In addition, we have demonstrated that these cells incorporate into the subretinal space long-term (up to 10 month), express VEGF Sticky-trap that a) remains bound to eye ECM and b) inhibits laser-induced chorodial NV. Here we have shown that the combination of stem cell and novel anti-VEGF gene therapy can inhibit neovascularization in a controlled and long-term manner; potentially improve vision, while avoiding the risk of side effects.
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