Summary: This laboratory investigates the molecular and cellular mechanisms of photoreceptor degeneration, age-related macular degeneration (AMD), and diabetic retinopathy with emphasis on the translation from bench work results to patient care.  We use experimental models that mimic human diseases to better understand the disease processes and to develop novel therapies. Several pre-existing models of retinal degeneration are being used in the laboratory. We have recently developed a model of choroidal neovascularization, a hallmark of wet AMD. We are currently creating a model of diabetic retinopathy. In addition, we are developing a cell-based assay using high throughput screen technologies to screen drug candidates for photoreceptor protection using available chemical libraries.

Rong Wen, M.D., Ph.D.
Research Associate Professor of Ophthalmology

View published research articles by this doctor in the National Library of Medicine.

Current Research Summary: Research in this laboratory is focused on three diseases in the retina, inherited retinal degeneration, age-related macular degeneration, and diabetic retinopathy. The long-term objective is to understand the diseases and to improve clinical treatments.

Inherited retinal degenerations are a major cause of blindness for which no effective treatments are available. It is estimated that one in 3,500 to 4,000 people is affected by retinitis pigmentosa (RP), a heterogeneous group of inherited retinal degenerative disorders. The major manifestation of RP is progressive degeneration of rod photoreceptors. During early stages, patients typically experience night blindness and decline in peripheral vision, due to loss of photoreceptors in the peripheral retina. Central vision is eventually affected as the degeneration progresses, leading to total blindness. Mutations in more than 100 genes are implicated in RP.

CNTF (ciliary neurotrophic factor) has been identified as a factor that promotes photoreceptor survival in a variety of animal models across several mammalian species. A phase I clinical trial has been completed in patients with RP and a phase II trial is underway. However, the mechanism that mediates CNTF effects is not clear. We have recently demonstrated that CNTF regulates the behavior of photoreceptors through Müller cell, a specific retinal glial cell believed to be the housekeeper of the retina. We also have evidence that CNTF promotes regeneration of the functional apparatus of cones (cone outer segments), the photoreceptor responsible for color and fine vision. Clearly, a better understanding of the mechanism will be not only important in basic retinal cell biology, but also essential for developing new therapeutic strategies for retinal degenerations. We are currently trying to understand the mechanism of Müller cell-photoreceptor interaction. We are also working on the details of CNTF induced regeneration of cone outer segments.

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in people over 65 of age in the western world. The exudative form of AMD (wet AMD) characterized by choroidal neovascularization (CNV), accounts for majority of the cases with severe loss of vision. We have recently developed an experimental model of CNV to closely mimic the human disease. By injecting Matrigel between photoreceptors and the RPE (retinal pigment epithelium), we have revealed a mechanism of sub-RPE deposit formation in which excessive material first accumulated in the subretinal space, disrupting the PRE-photoreceptors contact. RPE cells subsequently migrate toward photoreceptors and form a new layer to restore direct contact with photoreceptors. The subretinal material is consequently displaced to the sub-RPE location and becomes sub-RPE deposit. Our recent data also provide evidence that the presence of sub-RPE deposit is sufficient to induce choroidal neovascularization to penetrate Bruch’s membrane. In addition, we have used this model to screen drug candidates for wet AMD. One of the candidates is currently under development for clinical application. The current research with this model is to have a better understanding of the molecular mechanism of RPE cell migration.

Diabetic retinopathy remains a leading cause of severe vision loss and blindness in the developed world. Although in the early stage of the disease vision is not immediately impaired in patients, the proliferative stage of the disease could result in loss of vision due to leaky blood vessels in the retina that lead to edema and hemorrhage. Experimentally inducing diabetes in experimental models failed to induce proliferative retinopathy, however. The lack of suitable models has hampered the progress of diabetic retinopathy research and the development of new effective treatments. We are using a transgenic approach to circumvent the difficulty in inducing proliferative retinopathy in to mimic human diseases. Transgene constructs have been tested successfully in cultured cells and we expect to have transgenic soon. Full characterization of the newly created models is expected in the coming year.

Screening of new agents for photoreceptor protection is one of the research interests of this laboratory. The property of CNTF in protecting photoreceptors in many animal models encourages us to seek new drug candidates for retinal degenerations. The strategy is to use cell-based high-throughput screening facility to identify leads from available chemical libraries, which will be further confirmed in experimental models for photoreceptor protection and eventually for clinical evaluation. DNA constructs of reporters are made and cell lines containing the reporters to be used in the assay are established. We expect to conduct high-through put screening in a year or two.