DESCRIPTION : Primary open angle glaucoma (POAG) is the second leading cause of blindness in the United States. This disease is strongly age-related and affects approximately 1.9% of the US population 40 years or older and is highly prevalent in veterans. The development of elevated intraocular pressure (IOP) is closely associated with the development of glaucoma and results from increased resistance to aqueous humor outflow through the trabecular meshwork (TM). To date, there is no cure for glaucoma. Vision loss is permanent and while elevated IOP can be managed through medical or surgical means, it does not resolve permanently. Current medical treatment requires daily or twice daily application of one or more eye drops for the remainder of a patient's life. Despite the importance of maintaining a well-controlled IOP, patient compliance is poor, resulting in lack of IOP control and progressive vision loss. Elderly patients, in particuar, suffer from involuntary non-compliance due to the difficulty of applying the drops to their eyes. Lack of compliance is a major challenge in the clinical management of the disease and consequently the development of treatment modalities that lead to permanent, reliable IOP control is highly desirable. The overall goal of this project is to develop new approaches to restore healthy IOP in patients with glaucoma. Specifically we propose to evaluate whether replacement of damaged or lost trabecular meshwork (TM) cells with stem cell derived TM like cells can induce functional restoration following transplantation into glaucoma eyes. We hypothesize that replacement of lost or damaged TM cells with healthy cells can preserve or restore aqueous humor outflow facility, decrease IOP, and thus preserve vision. The source of these cells is, of course, crucial. A patient's native TM cells are difficult to obtain and may additionally be functionally compromised due to the effects of age-related stresses. We propose that the use of TM-like cells derived from induced pluripotent stem cell (iPSC-TM), which can be created from the patient's own dermal fibroblasts, obtained from a skin biopsy, offers the best solution to this challenge. In order to test our hypothesis we will induce iPSC to differentiate ito iPSC-TM and test them functionally in an ocular perfusion organ culture system. Human donor eyes will receive a transplantation of iPSC-TM and will be monitored for up to three weeks for integration of stem cells into the TM, changes in the eye's outflow capacity, and changes in the TM extracellular matrix. We will also test our hypothesis using a new mouse model of glaucoma which was recently developed by the P.I. and his collaborators. These mice, which develop elevated IOP due to a transgene expressing a pathogenic mutation myocilin, are uniquely suited for these studies because damage to the structure of their TM is mild even though TM cells become dysfunctional. This unique and novel approach could provide effective, permanent, vision saving treatment for veterans with POAG as well as other types of glaucoma, such as exfoliation glaucoma. Upon completion of these studies we expect to have obtained conclusive data to determine if TM regeneration using stem cell derived TM-like cells is an effective and safe approach that could be used to treat patients with glaucoma. We expect that the proposed study will point out novel treatment approaches for the prevention of vision loss in veterans who suffer from glaucoma that is difficult to manage or who face challenges preventing consistent use of IOP lowering medications.