J. Timothy Stout, M.D., Ph.D.
One of the most common causes of human blindness is abnormal, intraocular cellular proliferation that results in a loss of clarity of the visual axis or in a separation of the retina from the retinal pigment epithelium (retinal detachment). Proliferative retinal detachment, whether it is related to proliferative diabetic disease (PDR), retinopathy of prematurity (ROP) or proliferative vitreoretinopathy (PVR), if left untreated, ultimately results in permanent loss of vision.
The abnormal proliferation of new blood vessels within the eye, ocular neovascularization, is the most common cause of permanent blindness in developed countries. Three diseases are associated with the vast majority of all cases of intraocular neovascularization: diabetes, retinopathy of prematurity and age related macular degeneration. While these three clinical entities are distinct and affect different groups of patients, they share a final common pathway which involves the uncontrolled division of endothelial cells leading to the formation of new blood vessels which ultimately compromise retinal function. Together, these conditions account for approximately 60% of untreatable blindness in the United States. A major focus of our laboratory is to determine whether a variety of genes can be useful in modifying abnormal intraocular proliferation and, hence, decrease the incidence of neovascular disease, retinal detachment or visual axis opacification.
Our underlying hypothesis is that proteins, known to suppress unchecked cell division and unable to be inactivated by normal cellular mechanisms, can be used to transform cells in vivo and arrest the development of retinal detachment, intraocular neovascularization or post-cataract extraction capsular opacification. We employ viral and nonviral vectors to study the therapeutic efficacy of gene transfer in vivo. We have demonstrated an inhibitory effect on cell growth and division through the expression of constitutively active rb protein with ocular target cells. Recent work has demonstrated that this effect is observed in vivo.
While we have demonstrated an inhibitory effect on cell division with growth suppressor genes, we believe that other genes may be as or more useful, in certain clinical circumstances, in the in vivo inhibition of intraocular cell division. A variety of native modulators of blood new vessel growth (angiogenesis) have recently been identified. We believe that genetic control of the expression of these modulators may prove useful in the treatment of intraocular neovascular diseases, such as age-related macular degeneration, retinopathy of prematurity and proliferative diabetic retinopathy.
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