Decreased visual ability in veterans quickly leads to functional impairment and with it, reduced quality of life. In the year 2016 eye care was the third busiest clinical service in the VA Health Care system and 490,926 veterans receiving care at Veterans Affairs medical centers were given a glaucoma-related diagnosis. The most common type of the disease is primary open angle glaucoma (POAG), and the major risk factor for POAG is high intraocular pressure (IOP). Medical treatment is life-long and poor patient compliance presents a significant obstacle to successful care, motivating the need for novel safe, effective and sustained IOP control therapies. This project is designed with the long-term goal of regenerating the natural ability of the eye to regulate IOP. The trabecular meshwork (TM) is a key regulator of IOP and has been shown to undergo significant changes in POAG, including a loss of cells. This, in turn, causes failure of the tissue to carry out its functions and a subsequent rise in IOP. This motivates the use of cell therapy to restore TM function as a potential long- term treatment for POAG. Our studies have demonstrated that induced pluripotent stem cells (iPSC) can be differentiated into a cell type that resembles primary TM cells morphologically, compositionally, and functionally. Transplantation of these cells, designated iPSC-TM, into the eyes of mouse models of glaucoma causes re-celluarization of the TM, decreased IOP, and prevention of vision loss. This approach has also been shown to reliably increase TM cellularity in ex-vivo organ culture of human eyes obtained from older donors. These findings are extremely encouraging and suggest that restoration of TM function through iPSC-TM transplantation is possible. However, crucial aspects of iPSC-TM cell therapy require further development before translation into clinical practice can be considered. These include: (1) Increased targeting efficiency of transplanted material to the TM, which will reduce the number of injected cells and decrease off-target effects; (2) evaluation of the effectiveness and safety of allotransplants to reduce, which could reduce costs and increase quality of transplanted cells; and (3) direct demonstration that iPSC-TM cell therapy is effective in human eyes with POAG maintained in organ culture. Successful completion of our studies would provide a very strong rationale for future clinical trials. The proposed studies are highly innovative since they investigate a completely novel approach to permanently repair, rather than treat, glaucomatous damage in veterans. These studies will have an important impact since this unique and novel approach has the potential to profoundly alter clinical practice. Lasting functional restoration will reduce clinic visits and costs for the VA health care system, provide physicians with a new treatment option, and will help veterans through better vision and increased quality of life.