IOP homeostasis in glaucoma: Looking below the surface

This article was reviewed by Gaurang Patel, PhD

Until now, IOP elevations have been managed medically or surgically, but the most recent research is looking below the surface to get to the root causes of glaucoma.

Scientists at Regeneron Pharmaceuticals and Duke University have been collaborating to do just that and have identified 12 cell types that are involved in regulating the IOP and mapped region-specific expression of the candidate genes involved.

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According to Gaurang Patel, PhD, lead author of the study, glaucoma is a leading cause of irreversible blindness.

“It occurs when increased pressure inside the eye damages the optic nerve,” Patel said. “Current treatments alleviate that pressure, but it’s not fully known how it increases. We set out to identify the molecular structure of an area of the eye that helps regulate pressure.”

Importantly, while conventional treatments lower IOP and slows progression of the glaucoma, the progression of the visual field damage continues.

Patel and colleagues wanted to look past this to determine the hows and whys of dysregulation of the conventional outflow pathway in glaucoma.

According to Patel, using single-cell RNA sequencing, a high-throughput process that analyzes the RNA molecules expressed by genes, the team identified 12 distinct cell types in the trabecular meshwork [TM] and surrounding tissue.

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“The TM is a specialized area of eye tissue that acts like a membrane, regulating fluid outflow. If the eye is a sink, the trabecular meshwork is its drain,” he said. “How the drain gets ‘clogged,’ leading to high IOP and eventually the vision loss of glaucoma is not known. Better understanding of this very complex tissue may help lead to future treatment approaches for glaucoma.”

The investigators obtained the expression profiles of 17,757 genes from 8,758 cells in 8 human donor eyes.

By so doing, they identified 2 expression patterns, i.e., myofibroblast- and fibroblast-like, from the cells in the TM, which is the primary outflow pathway in the eye; they also found Schwann cell and microphase macrophage signatures in the TM.

Schlemm’s canal (SC) is the other primary component in the outflow pathway and it had a combination of lymphatic/blood vascular gene expression. They localized select glaucoma-related genes to the specific cell populations in the outflow tract.

Other expression clusters were found in cells in tissues adjacent to the TM and SC in the unconventional uveoscleral outflow pathway.

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“From the most abundant to the least, the cell signatures included Schwann cell-like, TM1 fibroblast-like, smooth muscle cell, TM2 myofibroblast-like melanocyte, macrophage, pericyte, vascular endothelial cell, T cell/natural killer cells, lymphatic-like endothelial cell, myelinating Schwann cell, and epithelial cell clusters,” the investigators reported.

Gene involvement
Many genes have been found to be involved in glaucoma. The investigators looked at a few to determine which cell clusters they were present in.

For example, the mutations in the MYOC gene cause glaucoma and angiopoietin-like 7, which has an elevated expression level in the aqueous in glaucomatous eyes.

In the current study, “MYOC was highly expressed in TM1, TM2, and smooth muscle clusters and was expressed at high levels in the TM and at lower levels in the ciliary muscle, Schlemm’s canal, and scleral fibroblasts.

Similarly, angiopoietin-like 7 was found in both TM1 and TM2 clusters, but the expression was more limited,” they reported.

The importance of this study is that the genes that are relevant in glaucoma were mapped to the genes in the conventional outflow pathway.

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The identification of 12 distinct cells types in and near the conventional outflow pathway emphasizes the diversity of the cells that are actively engaged in regulating the outflow function and IOP control.

The current findings may pave the way for developing novel glaucoma drugs for newly identified targets in glaucoma.

Read more by Lynda Charters

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Gaurang Patel, PhD
e:gaurang.patel@regeneron.com
Dr Patel is a shareholder in Regeneron Pharmaceuticals, and is an employee of Regeneron Pharmaceuticals in Tarrytown, New York.