Jason L. Vittitow

Genes expressed in the human trabecular meshwork during pressure‐induced homeostatic response

Physiological pressure inside the eye is maintained by a resistance mechanism provided by the trabecular meshwork tissue. In most cases, prolonged, elevated pressure leads to an eye pathology characterized by retinal ganglion cell (RGC) degeneration, optic nerve damage, and non‐remedial blindness. We are investigating the regulation of trabecular meshwork genes in response to elevated pressure. Using perfused organ cultures from postmortem human donors, we have previously demonstrated the presence of a homeostatic mechanism at 2–4 days of pressure insult (Borrás et al. 2002, Invest Ophthalmol Vis Sci 43:33–40). Here, we sought to identify trabecular meshwork genes whose expression was altered during this homeostatic period. By macroarray hybridization, we compared the expression profiles of high‐pressure (HP) and normal‐pressure (NP) treated eyes from the same individual (n = 3 pairs). Our results identified 40 upregulated and 14 downregulated genes. The highest proportion of upregulated genes encoded proteins involved in signal transduction (32%). Among the potentially relevant genes, PIP 5K1C, VIP, tropomodulin, and MMP2 encoded mediators known to influence outflow resistance. Others encoded functions which are new for the trabecular meshwork, but which are intrinsic to unrelated tissues. These new mechanisms appear as they could be of benefit for trabecular meshwork function. Matrix Gla protein (MGP), perlecan, osteomodulin, and osteoblast‐specific factor are essential in cartilage and bone physiology whereas spectrin and ICAM4 are specific for blood cells and crucial in maintaining their shape and adhesion. In addition, MGP transcripts were stimulated by extracellular calcium and downregulated by TGF‐β1. We propose that MGP might be an important player in the adaptive homeostatic mechanism by contributing to maintain a softer trabecular meshwork tissue and facilitate aqueous humor outflow. J. Cell. Physiol. 201: 126–137, 2004.

Nitric Oxide (NO): An Emerging Target for the Treatment of Glaucoma

The predominant risk factor for the progression of glaucoma is an increase in IOP, mediated via a reduction in aqueous outflow through the conventional (trabecular meshwork and Schlemms canal) outflow pathway. Current IOP lowering pharmacological strategies target the uveoscleral (nonconventional) outflow pathway or aqueous humor production; however, to date no therapy that primarily targets the conventional pathway exists. Nitric oxide (NO) is an intracellular signaling molecule produced by endogenous NO synthases, well-known for its key role in vasodilation, through its action on smooth muscle cells. Under physiological conditions, NO mediates a multitude of diverse ocular effects, including maintenance of IOP. Nitric oxide donors have been shown to mediate IOP-lowering effects in both preclinical models and clinical studies, primarily through cell volume and contractility changes in the conventional outflow tissues. This review is focused on evaluating the current knowledge of the role and mechanism of action of endogenous NO and NO donors in IOP regulation. Data on key additional functions of NO in glaucoma pathology (i.e., ocular blood flow and effects on optic neuropathy) are also summarized. The potential for future therapeutic application of NO in the treatment of glaucoma is then discussed.

A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study

Aim To assess the efficacy and safety of latanoprostene bunod (LBN) compared with latanoprost 0.005%, and to determine the optimum drug concentration(s) of LBN in reducing intraocular pressure (IOP) in subjects with open angle glaucoma or ocular hypertension. Methods Randomised, investigator-masked, parallel-group, dose-ranging study. Subjects instilled one drop of study medication in the study eye once daily each evening for 28 days and completed five study visits. The primary efficacy endpoint was the reduction in mean diurnal IOP at Day 28. Results Of the 413 subjects randomised (LBN 0.006%, n=82; LBN 0.012%, n=85; LBN 0.024%, n=83; LBN 0.040%, n=81; latanoprost, n=82), 396 subjects completed the study. Efficacy for LBN was dose-dependent reaching a plateau at 0.024%–0.040%. LBN 0.024% led to significantly greater reductions in diurnal IOP compared with latanoprost at the primary endpoint, Day 28 (p=0.005), as well as Days 7 (p=0.033) and 14 (p=0.015). The incidence of adverse events, mostly mild and transient, was numerically higher in the LBN treatment groups compared with the latanoprost group. Hyperaemia was similar across treatments. Conclusions LBN 0.024% dosed once daily was the lower of the two most effective concentrations evaluated, with significantly greater IOP lowering and comparable side effects relative to latanoprost 0.005%. LBN dosed once daily for 28 days was well tolerated. Clinical trial number NCT01223378.

Latanoprostene Bunod 0.024% in Subjects With Open-angle Glaucoma or Ocular Hypertension: Pooled Phase 3 Study Findings

Purpose: To compare the diurnal intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) 0.024% with timolol maleate 0.5% in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). Patients and Methods: Pooled analysis of two phase 3, randomized, multicenter, double-masked, parallel-group, noninferiority trials (APOLLO and LUNAR), each with open-label safety extension phases. Adults with OAG or OHT were randomized 2:1 to double-masked treatment with LBN once daily (qd) or timolol twice daily (bid) for 3 months followed by open-label LBN treatment for 3 (LUNAR) or 9 (APOLLO) months. IOP was measured at 8 AM, 12 PM, and 4 PM at week 2, week 6, and months 3, 6, 9, and 12. Results: Of the 840 subjects randomized, 774 (LBN, n=523; timolol crossover to LBN, n=251) completed the efficacy phase, and 738 completed the safety extension phase. Mean IOP was significantly lower with LBN versus timolol at all 9 evaluation timepoints during the efficacy phase (P<0.001). A significantly greater proportion of LBN-treated subjects attained a mean IOP ⩽18 mm Hg and IOP reduction ≥25% from baseline versus timolol-treated subjects (P<0.001). The IOP reduction with LBN was sustained through the safety phase; subjects crossed over from timolol to LBN experienced additional significant IOP lowering (P⩽0.009). Both treatments were well tolerated, and there were no safety concerns with long-term LBN treatment. Conclusions: In this pooled analysis of subjects with OAG and OHT, LBN 0.024% qd provided greater IOP-lowering compared with timolol 0.5% bid and maintained lowered IOP through 12 months. LBN demonstrated a safety profile comparable to that of prostaglandin analogs.