Speaker: Nitric oxide signaling is important to glaucoma

Louis R. Pasquale

ORLANDO, Fla. – Nitric oxide signaling biomarkers contribute to glaucoma by causing increased IOP and vascular insufficiency, Louis R. Pasquale, MD, FARVO, hypothesized here at the Optometric Glaucoma Society meeting, held prior to the American Academy of Optometry meeting.

Pasquale, a professor of ophthalmology at the Icahn School of Medicine at Mt. Sinai, shared a case of a middle-aged Asian female with primary open angle glaucoma (POAG) who was told by a dermatologist that she had some type of fungal infection in her fingernails. Pasquale ordered nailfold capillary imaging and found she had massive avascular zones.

He and his colleagues found in a study that 80% of patients with POAG, regardless of IOP, had a hemorrhage in their nail per 100 capillaries, while only 30% of those without POAG did.

“Nitric oxide is needed at points of high shear stress in vascular beds,” Pasquale said. “You need nitric oxide to keep these blood vessels open. You can imagine in the optic nerve head if you don’t have enough nitric oxide – a lot of these events are happening.”

Pasquale continued: “There’s a lot of evidence to suggest that nitric oxide signaling is important to POAG. POAG patients demonstrate impaired retinal vascular autoregulation, blunted brachial artery vasodilation in response to acetylcholine and nailfold capillary morphological abnormalities.”

Pasquale, with Wareham and colleagues, evaluated tadalafil in a murine POAG model. Their hypothesis was that “potentiation of cGMP levels, which is central to nitric oxide signaling, protects retinal ganglion cells from dying,” he said.

They found that tadalafil did not alter IOP in controls or glaucoma models; however, it prevented retinal ganglion cell body and axon loss in the murine POAG model at 10 months.

He concluded: Genetic determinants in the nitric oxide signaling pathway are related to POAG and primary angle closure glaucoma; murine models confirm that nitric oxide signaling molecules are implicated in IOP regulation and optic nerve homeostasis; and targeting the nitric oxide signaling pathway afforded structural neuroprotection in two preclinical glaucoma models.

This is a very druggable pathway, Pasquale said, but are we ready for a randomized clinical trial?

“We’re writing that proposal,” he said. “Tadalafil is the most expensive of erectile dysfunction drugs, but it just went off patent. We’ll have to address issues with side effects and we’ll need to get funding. The plan is to do a short-term study first, looking at OCT angiography and nailfold capillary blood flow before going on to a randomized clinical trial.” – by Nancy Hemphill, ELS, FAAO

References:

Pasquale LR, et al. Invest Ophthalmol Vis Sci. 2015;doi:10.1167/iovs.15-17860.

Pasquale LR. The role of nitric oxide in glaucoma. Presented at: Optometric Glaucoma Society meeting; Orlando, Fla.; October 22, 2019.

Wareham LK, et al. Neurobiol Dis. 2018;doi.org/10.1016/j.nbd.2018.09.002.

Disclosure: Pasquale reports he is an advisor to Bausch + Lomb, Emerald Bioscience, Eyenovia and Verily.