Tissue plasminogen activator for the treatment of glaucoma

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Open angle glaucoma (OAG) is a group of progressive optic neuropathies that can lead to blindness. It is a serious health issue among minorities and veterans who are disproportionately affected by the disease. OAG pathology involves increased IOP which is the result of reduced outflow facility of the aqueous humor. High IOP increases the risk for both development and progression of glaucomatous neurodegeneration and functional loss. Although current therapies of OAG are directed at lowering IOP, few if any target the site of pathology in the outflow tissues or increase outflow facility. Tissue plasminogen activator (tPA) is a serine protease that has an important role in outflow facility regulation. We have shown that tPA is reduced in steroid-induced IOP elevation and that outflow facility is reduced in tPA (PLAT)-null animals. Furthermore, exogenous supplementation of tPA reverses outflow facility reduction and IOP elevation in both steroid-induced glaucoma as well as in tPA null animals. We have also surprisingly shown that tPA and enzymatically inactive tPA (EI-tPA) can improve outflow facility in human mutant myocilin transgenic animals. We propose here to determine the efficacy and safety of using tPA and EI-tPA as a long-term treatment for OAG, and elucidate the molecular mechanisms through which tPA causes its effect on outflow facility. Our hypothesis is that overexpression of EI-tPA in the outflow tissues is safe and effective in the treatment of OAG and results in preservation of vision. Furthermore, we hypothesize that EI-tPA causes matrix metalloproteinase 9 (MMP9) upregulation through the Low-density lipoprotein Receptor-related Protein (LRP) receptors and Extracellular signal-Regulated Kinase (ERK) signaling. To test this hypothesis, we propose the following specific aims: Specific Aim 1: Determine whether chronic treatment with tPA or EI-tPA can be used to treat glaucoma and prevent functional damage from the disease. Specific Aim 2: Determine whether chronic treatment with tPA or EI-tPA causes retinal or other eye toxicity or has adverse effects on function. Specific Aim 3: Determine whether LRP mediated ERK activation is responsible for the tPA induced MMP9 upregulation in vivo. The proposed studies will allow us to better understand the mechanisms of outflow facility regulation by tPA and determine whether an enzymatically inactive variant can be used for chronic therapy of OAG to prevent functional visual loss from the disease. It is thus expected to significantly contribute to the health and well-being of veterans who are known to be disproportionately affected from glaucoma