Last year saw some of the first new innovations in topical glaucoma treatment hit the market with the introduction of nitric oxide in Vyzulta (latanoprostene bunod, Bausch + Lomb) and rho-kinase inhibitors in Rhopressa (netarsudil, Aerie).
Behind the scenes, these new additions to our treatment options reveal a bigger mindset change in what is happening in our scientific understanding of glaucoma as a disease process.
In this podcast, Jennifer Lyerly, OD, and Darryl Glover, OD, sit down with Cynthia Steel, PhD in cell biology and anatomy, and a 10-year veteran of glaucoma research.
Glaucoma treatment innovations
The last major innovations in topical glaucoma treatment occurred in the early 2000s when prostaglandin analogues hit the market, quickly becoming the new first-line treatment modality for open-angle glaucoma patients.
Why has it taken two decades for new innovations to enter the marketplace and for those new additions to be more adjunctive rather than full-scale replacement of prostaglandins?
Dr. Steel cites two major challenges facing researchers in the field:
• Lack of good animal models to study glaucoma as a process. Because the causes of glaucoma are multifactorial, mimicking and recreating the process that happens in this disease to study it in animals is inherently limited in its ability to capture the full complexity of glaucoma.
• Obtaining funding for research is increasingly difficult. In today’s healthcare marketplace, finding cures is essential to the financial bottom-line of companies investing in research. With glaucoma, where research is still trying to establish what is even happening in the disease, proposing a study that could find a cure for glaucoma is understandably far-fetched. But if studies modeling what happens in the glaucoma process can’t get funded, researchers and clinicians are left with the minimal knowledge they have now.
Role of TM
Early in her career, Dr. Steel focused on the anterior segment and the trabecular meshwork (TM) specifically.
TM cells are like no other cells in the body. They are derived from and shaped like endothelial cells, they but contract like smooth muscle cells. They act like macrophages; their innate phagocytic activity allows them to create a tissue that acts like a self-cleaning filter.
Scientists have known for years that the TM was an essential structure to unlocking a treatment breakthrough for glaucoma, even back in the early 2000s when prostaglandins were taking over the market. Prostaglanins analogues target only uveoscleral outflow, which is a much smaller pathway than flow of the aqueous humor through the TM.
In 2019, the working model of primary open-angle glaucoma is that dysfunction in the TM is a key cause of why intraocular pressure (IOP) increases to dangerous levels. The TM cells have mechanosensors to detect changes in IOP and then self-regulate outflow of aqueous humor through the TM to maintain IOP homeostasis.1 In glaucoma, this system malfunctions.
Over our lifespan, the TM becomes stiffer and more rigid as extracellular matrix tissue continues to be laid down around the cell walls of TM cells.2 This thickening of the extracellular matrix layer causes TM cells to be les able to detect IOP changes and creates more resistance to aqueous humor flowing through the TM tissue. The entire system becomes dysregulated.
Key to our understanding of this process is an appreciation for the importance of the aqueous humor. The aqueous humor is a “blood surrogate” for anterior segment and TM tissue. As doctors, we know that the TM should not have blood vessels-if we see neovascularization of the tissue, it’s a sign of a significant concern.
Instead of getting oxygen and nutrients from blood, TM cells are supported with everything they need from the aqueous humor that passes through the tissue matrix. If the TM stiffens with excess extracellular matrix, less aqueous humor (and the vital oxygen and nutrients it carries) is passing through the system and can eventually lead to cell death. This is glaucoma.
Historically, treatment options have been focused on lowering IOP, but in the future, Dr. Steel proposes that our focus may shift to how to restore IOP homeostasis and keep the TM tissue healthy and functional.
For example, knowing that aqueous humor is the nutritional supply to the anterior segment tissue, is suppressing aqueous humor production a safe long-term approach to glaucoma treatment and maintaining tissue health? In the future, treatment that focus on this suppression pathway may be relegated to more end-stage disease because we have better treatments to maintain healthy tissue in early disease intervention.
New treatment possibilities
New studies suggest innovative new treatment possibilities in glaucoma.
• Eating green leafy vegetables is associated with a lower risk of primary open-angle glaucoma.3 This literature review study used data from 100,000 participants; people who ate the most leafy greens in their diet were 18 percent less likely to develop any form of open angle glaucoma, and 48 percent less likely to develop low pressure or normal tension glaucoma.
Why? Leafy greens are rich in nitrates, and higher dietary nitrates result in better vascular health and lower blood pressure. In addition to prescribing topical treatments, discussing nutritional and cardiovascular health is warranted for glaucoma patients. Treatments that increase nitric oxide or dietary nitrates may play a larger role in glaucoma management going forward, especially for patients with low or normal tension glaucoma.
• Nicotinamide (vitamin B3) could be neuroprotective in glaucoma.4 Protecting the optic nerve tissue has long been a goal of glaucoma treatment, but the reality of neuroprotection has been a source of hot debate for decades in glaucoma. New research published in 2018 resurfaced the idea with a new player: nicotinamide. Research suggests that mitochondrial dysfunction is the potential origin of retinal ganglion cell death; nicotinamide adenine dinucleotide (NAD) is a key component of mitochondrial metabolism. Lower amounts of NAD make retinal ganglion cells more vulnerable to stress, like that caused by elevated IOP. Human clinical trials are underway to see if this model plays out with real results in patients.
1. Goel M, Sienkiewicz AE, Picciani R, Wang J, Lee RK, Bhattacharya SK. Cochlin, intraocular pressure regulation and mechanosensing. PLoS One. 2012;7(4):e34309.
2. Acott TS, Kelley MJ. Extracellular matrix in the trabecular meshwork. Exp Eye Res. 2008;86(4):543-61.
3. Kang JH, Willett WC, Rosner BA, Buys E, Wiggs JL, Pasquale LR. Association of Dietary Nitrate Intake With Primary Open-Angle Glaucoma: A Prospective Analysis From the Nurses’ Health Study and Health Professionals Follow-up Study. JAMA Ophthalmol. 2016;134(3):294-303.
4. Cimberle M. Nicotinamide shows promise as neuroprotective treatment for glaucoma. Ocular Surgery News. Available at: https://www.healio.com/ophthalmology/glaucoma/news/print/ocular-surgery-news/%7Bd5ab4311-cea9-4379-a823-266b82ce321f%7D/nicotinamide-shows-promise-as-neuroprotective-treatment-for-glaucoma. Accessed 1/25/18.