The Role of the Rho-Kinase Pathway in Proliferative Vitreoretinopathy
Abstract
The overarching goal of this proposal is to address the lack of effective treatment for proliferative vitreoretinopathy (PVR), a primary cause of severe and irreversible visual loss in ocular trauma patients. The incidence of blindness from PVR is especially high among active Service Members due to the combat-related risks of exposure to explosive devices, blast, and projectiles. PVR occurs when breaks and tears in the retina, caused by trauma-induced retinal detachment and perforating injuries, disrupt the retinal pigment epithelial cells (RPE) and neighboring cells, and place them in direct contact with the intraocular vitreous fluid. To date, the only treatment for PVR is the surgical removal of the membranes and reattachment of the retina. However, success of corrective surgery for PVR is low as invasive treatment and surgical peeling of the membranes further damage the retina promoting recurrent PVR and low visual outcomes. The development of safe and efficient adjunctive medical treatments for PVR is therefore critical to reduce the prevalence of blindness following ocular injuries. Targeting the key cellular processes involved in the activation of cells involved in the formation of PVR is a promising strategy for the treatment of PVR. The Kim laboratory has identified that PVR membrane formation is associated with the activation of the Rho-Kinase pathway. Using a model of PVR, we found that cells derived from human PVR membrane samples show a higher activation of Rho-Kinase in our PVR model. We found that Rho-Kinase inhibitors have therapeutic potential in blocking the contractile and migratory properties of PVR cells. Importantly, the Rho-Kinase inhibitor, netarsudil, is already commercially available for glaucoma and could be repurposed and readily deployed for PVR treatment. To ensure the success of this project, we have assembled a team of scientists and clinicians who are experts in the molecular mechanisms of retinal injury as well as experimental and clinical PVR. Completion of this proposal has strong potential to determine the efficacy of Rho-Kinase inhibitors to combat PVR and identify novel therapeutic targets, surrogate biomarkers, and strategies for efficient prevention or treatment of PVR. We expect that these findings will provide the necessary validation for the subsequent evaluation of Rho-Kinase inhibitors for clinical applications and have already established collaborations with clinicians to facilitate translational development. Our proposed work will have an important beneficial impact on active Service Members, Veterans, and civilians by reducing the risk of vision loss from ocular trauma thereby improving their quality of life and well-being.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310527
Entities
People
- Leo Kim
Organizations
- Schepens Eye Research Institute
- United States Army