Outflow Signaling Mechanisms and New Therapeutic Strategies for the Control of Intraocular Pressure

I. OVERVIEW

Tens of millions of the world’s population are inflicted with glaucoma, a sight threatening disease. One major risk factor for the development and progression of glaucoma is abnormally elevated intraocular pressure, which is a result of impeded outflow of aqueous humor. Understanding the regulation of aqueous outflow and its improvement have become urgent needs in the development of future treatments for this disease. This review discusses the potential pathological events involved in primary open angle glaucoma, while focusing on relevant molecular and cellular mechanisms. This review further describes the various on going and novel therapeutic strategies being designed and evaluated for enhancement of aqueous outflow.

II. INTRODUCTION

Glaucoma is one of the leading causes of blindness in the world, estimated to aVect 60 million individuals worldwide in 2010 and 80 million by 2020. Among them, 14% will develop bilateral blindness (Quigley and Broman, 2006). This disease is a complex, age related, and inherited optic neuropathy with characteristic slow progressive loss of retinal ganglion cells and excavation of the optic disc. Among the risk factors, such as age, race, and family history, that are associated with glaucoma, elevated intraocular pressure (IOP) is the most pivotal. Although not all patients with elevated IOP (>21 mmHg) develop glaucoma, the occurrence of glaucoma increases significantly with increased IOP. Ocular hypertension in glaucoma is a result of a reduction in aqueous humor outflow facility, concomitant with biochemical and morphological changes in the trabecular meshwork (TM).

A. Ocular Hypertension: A Major Risk Factor of Glaucoma

Many prospective and randomized clinical trials have consistently demonstrated that lowering IOP is important in slowing the progression of glaucoma, as well as preventing and delaying its onset. The Advanced Glaucoma Intervention Study (AGIS) showed that, regardless of treatment strategies, patients with higher mean IOPs had a faster disease progression than those with lower IOPs. Most importantly, the subset of patients with IOPs below 18 mmHg at all visits had no or minimal progression during the 6 year follow up period (AGIS Investigators, 2000). Likewise, in the Collaborative Initial Glaucoma Treatment Study (CIGTS), in which newly diagnosed glaucoma patients were randomized to initial treatment with topical ocular

medicines or glaucoma filtration surgery, there was little disease progression over the course of 5 years in individuals with the greatest reduction in IOP (Lichter et al., 2001). The Early Manifest Glaucoma Treatment Trial (EMGTT) evaluated the eVect of IOP lowering therapy in patients with early glaucoma. The treated group had approximately half the risk for glaucoma progression relative to the untreated patients (Leske et al., 2003). The clinical benefit of controlling IOP extends to patients with normal tension glaucoma, whose IOP is considered within the normal range (<21 mmHg). The Collaborative Normal Tension Glaucoma Study (CNTGS) demonstrated that lowering IOP in this patient population also reduced disease progression (CNTGS Group, 1998). In addition to slowing down its development and progression, lowering IOP prevents or delays the onset of glaucoma as well. In the Ocular Hypertension Treatment Study (OHTS), 50% of the enrolled ocular hypertensive patients received IOP lowering treatment, while the other patients were untreated. After a 5 year follow up period, the treated individuals were twofold less likely to develop glaucoma, indicating that lowering IOP prevented or delayed the onset of glaucoma (Kass et al., 2002). The obvious conclusion from all these well designed clinical studies is that high IOP is associated with an increased risk of glaucomatous damage and lowering it reduces such risk. There should also be no doubt that a robust IOP reduction is a necessary and eVective treatment in most glaucoma patients.

B. Fluctuation of IOP

In addition to high IOP, IOP fluctuation has also been proposed as an independent risk factor for glaucoma. In the AGIS, long term (months and years) fluctuation of IOP was shown to be a strong and independent predictor of visual field deterioration (Nouri Mahdavi et al., 2004). Many other prospective studies also found that ocular hypertension and IOP fluctuation are correlated with glaucoma progression (O’Brien et al., 1991; Bergea et al., 1999; Stewart et al., 2000). Recently, Hong and colleagues further demonstrated that even in glaucoma patients with low IOP (<18 mmHg; controlled by surgery), long term IOP fluctuation was a risk factor for the decline of visual field (Hong et al., 2007). However, not all studies support this correlation. Analyses of data of the EMGTT and OHTS did not detect an independent link between IOP fluctuation and glaucoma progression (Bengtsson et al., 2007; Gordon et al., 2007). To reconcile these diVerences, Caprioli hypothesized that IOP fluctuation is the prominent risk factor in patients with lower IOP, but when the IOP is high (as those in the EMGTT and OHTS), the mean IOP became the predominant risk factor (Caprioli, 2007).

Currently, the mechanism of glaucomatous damage induced by IOP fluctuation is yet unclear. However, as compared to a constant state of stress, the large IOP fluctuation may cause ever changing stress levels that the aVected ocular tissues cannot compensate eVectively and thus become damaged.

C. Regulation of IOP

Pressure in the eye is balanced by an equilibrium between aqueous humor formation and its outflow, as described by the Goldmann equation.

Goldmann equation : IOP ¼ ðF UÞ þ Pe

C

where F is the aqueous humor formation rate, U is the uveoscleral outflow rate, C is the trabecular outflow facility, and Pe is the episcleral venous pressure.

An excessive production of aqueous humor and/or a reduction of its outflow could cause ocular hypertension. However, there are no clinically relevant diVerences in rates of aqueous humor production between glaucomatous and normal individuals. In glaucoma and ocular hypertensive patients, various studies indicated that the cause of IOP elevation is a reduction in aqueous outflow (Langham, 1979; Segawa, 1979; Rohen, 1983).

D. Aqueous Outflow Pathways

After being produced in the ciliary epithelium, aqueous humor travels from the posterior chamber, through the pupil, then enters the anterior chamber. Along the route, it helps to maintain the metabolic homeostasis of the neighboring ocular tissues. Aqueous humor leaves the eye through two major aqueous outflow pathways: the trabecular pathway and the uveoscleral pathway.

1. Trabecular Pathway

The trabecular pathway, which is also called the conventional outflow, involves the TM and the Schlemm’s canal in the eye. The TM is located at the anterior chamber angle bordered by the cornea and iris. It is a meshwork formed by strands of collagenous sheets and beams populated with TM cells, with microscopically open spaces between the beams. The Schlemm’s canal is a ring like channel of irregular diameter. It has an endothelium lined lumen surrounded by a thin discontinuous basement membrane. The aqueous