Nitric oxide: A potential target for glaucoma treatment

Take-home message: Evidence suggests that nitric oxide can modify both mechanical and vascular events in primary open-angle glaucoma pathogenesis.

By Michelle Dalton, ELS; Reviewed by Emmanuel Buys, PhD

Boston-“Nitric oxide (NO) donors” may be a new term for some ophthalmologists, but researchers have known for some time NO donors can relax the trabecular meshwork (TM) and help increase aqueous humor (AqH) outflow. There has been some experimental data that suggest NO donors can modulate IOP through the conventional pathway. NO is a colorless, odorless gas that is slightly water soluble, and soluble guanylate cyclase (sGC) is a known NO target, said Emmanuel Buys, PhD, assistant professor of anesthesia, Massachusetts General Hospital.

Dr. BuysNO is considered an “exceptionally well-characterized signaling molecule,” and its importance in various physiological processes (including cardiovascular homeostasis, neuronal function, and inflammation) is well documented. NO is a key component in regulating apoptosis, vascular tone, and inflammatory responses and has been much better studied outside the eye. It is synthesized by a family of enzymes (the NO synthases, or NOS) and various NOS isoforms have been expressed in the TM, ciliary muscle, retina, and optic nerve, Dr. Buys said, making NO a potential target for glaucoma.

“Under physiological conditions, the low levels of NO produced by the two constitutive calcium-dependent enzymes NOS1 and NOS3 have diverse functions ranging from neurotransmission and vasodilation to inhibition of platelet adhesion and aggregation,” he said. “The presence of NOS3 and sGC in the ciliary muscle and the TM suggest that the NO-sGC pathway may modulate outflow resistance by regulating the ciliary muscle and TM contractility.”  

In addition, current evidence suggests that NO can modify both mechanical and vascular events in primary open-angle glaucoma pathogenesis.¹

The NO function and glaucoma

In mouse studies, NOS3 overexpression lowered IOP by increasing pressure-dependent drainage, and preclinical studies demonstrated the ability of NO-donor compounds (including NO-donating prostaglandins and glucocorticoids) to lower IOP, Dr. Buys said. Studies from the early 2000s reported lower levels of NO metabolites and cGMP levels in both plasma and AqH levels in people with primary open-angle glaucoma compared to people without glaucoma.

“Exactly how NO-cGMP signaling regulates IOP or impacts optic neuropathy remains unclear,” Dr. Buys and co-authors said.² To complicate matters, NO also may have neurotoxic effects on retinal ganglion cells; in acute angle-closure glaucoma, higher levels of NO in the AqH were thought to cause optic nerve and ganglion cell damage.²

In an exciting development, two phase 3 studies of latanoprostene bunod, an NO-donating prostaglandin F2-alpha analog, lowered IOP more than twice-daily timolol in patients with POAG or ocular hypertension. Bausch + Lomb (Bedminster, NJ) submitted Vesneo (latanoprostene bunod) in July 2015 for U.S. approval based on positive pivotal phase 3 study outcomes (n=850 patients) that included a reduction in mean IOP of 7.5 mm Hg to 9.1 mm Hg from baseline with 2 and 12 weeks of treatment.

Studies have shown NO donors to elicit a “dose-dependent biphasic effect on trabecular meshwork relaxation and a reduction in myosin light chain-2 phosphorylation.”³

Increasing NO levels may increase outflow and lower IOP in a similar manner as other compounds under investigation, including the Rho-kinase drugs, Dr. Buys said.

“Inhibiting Rho-kinase and activating sGC with NO likely have the same net effect on smooth muscle relaxation,” he explained.

However, he hypothesizes that NO has “multiple sites of activity that are possible of therapeutic benefit, when compared to the rather singular mode of action of the Rho kinase inhibitors.”

For example, he said, NO may increase outflow in the anterior segment, which in turns lowers IOP, and is generally a well-accepted theory.

“Perhaps a bit more speculative, however, is that NO can increase blood flow in the retina, thereby preventing ischemia and accompanying retinal degeneration, which is relevant in light of the hypothesis that there is an important vascular component to the etiology of at least some subtypes of glaucoma,” Dr. Buys said. “Finally, in light of the abundant expression of sGC in retinal ganglion cells, one might speculate on the possible neuroprotective role of sGC (and its activation by NO) in those ganglion cells.”

Study findings

In one study,¹ Dr. Buys’ group evaluated whether the presence of any of 51 known single nucleotide polymorphisms (a DNA sequence variation occurring commonly within a population in which a single nucleotide in the genome differs between individuals) in the gene encoding sGC is associated with the presence of glaucoma, and found some correlations.

“We found that the rs11722059 SNP is indeed associated with a subtype of primary open-angle glaucoma, characterized by early paracentral visual field loss, in women,” he said. “Although these results suggested there might be a link between POAG and sGC, this study had limitations.”

He recommended the study be replicated, and said it remains unclear what the functional effect of the SNP is, or if the associated SNP is in another gene.

References

• 1.     Buys ES, Ko Y-C, Alt C, et al. Soluble Guanylate Cyclase a1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma. PLoS ONE 8(3): e60156.

• 2.     Buys ES, Potter LR, Pasquale LR, Ksander BR. Regulation of intraocular pressure by soluble and membrane guanylate cyclases and their role in glaucoma. Frontiers Mol Neurosci. 19 May 2014.

• 3.     Cavet ME, Vollmer TR, Harrington KL, VanDerMeid K, Richardson ME. Regulation of endothelin-1-induced trabecular meshwork cell contractility by latanoprostene bunod. Invest Ophthalmol Vis Sci. 2015;56:4108-4116.

Emmanuel Buys, PhD

Dr. Buys has no financial disclosures, but Massachusetts General Hospital has filed a provisional patent application of iNO gas as an IOP-lowering agent. Dr. Buys’ laboratory work can be found at http://buyslab.mgh.harvard.edu