Last year saw some of the first new innovations in topical glaucoma treatment hit the market, with the introduction of nitric oxide in Vyzulta and rho-kinase inhibitors in Rhopressa. Behind the scenes, these new additions to our treatment modality reveal a bigger mindset change is what is happening in our scientific understanding of glaucoma as a disease process.  In this podcast, Dr. Jennifer Lyerly and Dr. Darryl Glover sit down with Dr. Cynthia Steel, PhD in Cell Biology and Anatomy, and a 10 year veteran of glaucoma research.

The last major innovations in topical glaucoma treatment occurred in the early 2000s as 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:

* There is a lack of good animal models to study glaucoma as a process. Because the causes of glaucoma as so 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.

* Getting funding for research is increasingly difficult in today’s healthcare marketplace, where finding cures is essential to the financial bottom-line of companies investing in your 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, we’re stuck with the minimal knowledge we have now.

Early in her career, Dr. Steel became especially 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, 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 that the TM was an essential structure to unlocking a treatment breakthrough for glaucoma for years, even back in the early 2000s when prostaglandins were taking over the market. Prostaglanins analogues only target uveoscleral outflow which is a much smaller pathway than flow of the aqueous humor through the TM.

In 2019, our 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.  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. This thickening of the extracellular matrix layer causes TM cells to be les able to detect IOP changes, and also creates more resistance to aqueous humor flowing through the TM tissue. The whole 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 neovascula...