br Pathophysiology of glaucoma Glaucoma is
Pathophysiology of glaucoma Glaucoma is a group of optic neuropathies defined by progressive degeneration of RGCs and their DLPC synthesis in the optic nerve, which leads to irreversible loss of vision [3,8,9]. RGC degeneration is often significantly advanced before changes in visual acuity and evidence of optic nerve cupping are detected in the clinic [, , ]. Although the pathogenesis of glaucoma is not well understood, progression correlates with IOP, regardless of whether IOP is normotensive or hypertensive . Several clinical trials indicate that IOP-lowering drugs are effective in delaying progression of the disease. In particular, the Early Manifest Glaucoma Trial (EMGT) indicates that the risk of progression decreases by approximately 10% with each 1 mmHg IOP reduction from baseline . Similarly, the Ocular Hypertension Treatment study indicates that a 20% reduction in IOP is effective in delaying or preventing the onset of POAG in patients with ocular hypertension . Thus, lowering IOP remains the primary course of treatment for glaucoma patients as well as for those with ocular hypertension deemed at-risk for glaucoma. Our current understanding of the relationship between IOP and RGC degeneration indicates that IOP elevation leads to a corresponding increase in pressure exerted posteriorly at the optic nerve head, where the optic nerve exits the globe of the eye [15,16]. The lamina cribrosa, a band of extracellular matrix in the optic nerve head, marks the beginning of the optic nerve and is prone to compression, deformation, and remodeling induced by mechanical strain related to IOP. This compressive deformation is transferred to RGC axons, which pass through perforations in the lamina cribrosa as they exit the globe. Studies in animal models of glaucoma indicate that ocular hypertension results in the disruption of both anterograde and retrograde transport in RGC axons, particularly near the optic nerve head . These studies are corroborated by structural changes in RGC axons of the optic nerve head from human donors with glaucoma . Interestingly, studies in animal models indicate that deficits in axon transport occur early in glaucoma progression, prior to structural degeneration of RGC axons and soma [3,18]. These studies suggest that the interval between changes in axon transport and structural degeneration of RGCs may constitute a window for therapeutic intervention. While glaucoma is typically diagnosed in patients already exhibiting 40–50% visual field loss [19,20], the cellular process of degeneration is occurring at various rates throughout the RGC population. If targetable, this therapeutic window provides the opportunity to interrupt degeneration in RGCs within glaucomatous retina that have not yet progressed to structural degeneration. Thus, there is the possibility of preserving RGCs and preventing further vision loss, independent of or in addition to IOP management.
Why the need for new medications? IOP is established by the balance of AqH production and elimination from the anterior chamber. Two independent pathways regulate AqH dynamics: the conventional pathway and the unconventional pathway. In humans, the majority of AqH drainage occurs via the trabecular meshwork (TM) and Schlemm's canal (SC), which constitute the conventional pathway  (Fig. 1). However, it has been estimated that across different species, around 3–82% of AqH drainage can also occur via the uveoscleral tract of the unconventional pathway [, , , , , ]. The first course of treatment to lower IOP is usually through topical application of drugs that modulate AqH dynamics by: 1) reducing AqH production 2) increasing uveoscleral outflow or 3) increasing flow through the conventional pathway via contraction of the ciliary muscle (CM) . Issues with patient compliance and side effects can reduce efficacy of topical drugs. Accordingly, sustained delivery platforms, such as the bimatoprost intracemeral slow-release implant, are already in phase III clinical trials . Alternative strategies for IOP management are currently surgical, i.e. laser trabeculoplasty or incisional glaucoma surgery .