Development of therapeutic agents and gene therapy by inhibiting new vessel formation

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In the pathogenesis of diabetic retinopathy, hyperglycemia causes breakdown of vascular barrier function and retinal ischemia. Retinal edema and bleeding follow the breakdown of vascular barrier. In addition to retinal endothelial damage and abnormality of blood coagulation, severe retinal edema acceleratesthe retinal capillary obstruction andretinal ischemia. The epidemiological investigation of the patients visiting Yamagata University Hospital revealed tha the progression of retinopathy causes the vision, which has suggested that the prevention of new vessel formation is very important. The vasculopathy in diabetic retinopathy is based on many cytokines and growth factors, including vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β) superfamily and others. To prevent the new vessel formation, we investigated the methods to regulate the funtions of vascular endothelial cells. The extracelluar matrix (ECM) formation is related to the cell funtions and ECM … More is regulated by cytokines. The present study has revealed ethat the hyaluronan formation is regulated by hyaluronan synthase (HAS), and HAS is regulated by TGF-β and PDGF-BB.The regulation of HAS acitiity by TGF-β is one of the candidates to regulated new vessel formation. The clinical study using vitreous somples obtained during vitrectomy has revealed that the ocular new vessel formation is regulated by the balance between the angiogentic factor and angiostatic factors. We have shown that activin A was expressed in the vitreous and acted as angiostatic factor. The concentration of activin A was too low to inhibit the new vessel formation. The transfection of activin receptors improved the responsibility of the endothelial cells, which may be another candidates of gene therapy. Another strategy to inhibit new vessel formation is to regulate the pericytes. The proliferation of pericytes is inhibited by TGF-β and stimulated by plasmin. These 2 factors competed each other. The regulation of pericytes is also another candidates of gene therapy. The Expressions of VEGF, PlGF, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the vitreous obtained from PDR eyes were investigated. The correlation among cytokines/growth factors and clinical characteristics was inquired to know the roles in the pathogenesis of diabetic retinopathy. These factors were correlated each other. These evidences proposed the issue that it is mandatory to investigate the main target to develop the methods of the gene therapy from now on. Less