Mechanism of IOP elevation in POAG explored

"One can add abnormal resistance at any site of normal outflow resistance in the outflow pathway and cause glaucoma, and therefore there's likely more than one cause of what we all call primary open-angle glaucoma," Dr. Epstein said.

In fact, efforts to understand IOP elevation and the outflow pathway better should lead to new forms of glaucoma therapy, he continued.

"With renewed interest in the role of IOP in the pathogenesis of glaucoma, it is important to try to understand the reason why the IOP might be elevated," he said.

The histopathology of POAG has revealed two main findings, he said. The first is the presence of extracellular plaque material, which is thought to be a secondary phenomenon. The second is decreased trabecular meshwork cellularity, first described by Jorge Alvarado, MD, which may have a more primary impact.

Investigators are still exploring the role of these cells, seeking to determine the meaning of cell loss and the function of the outflow pathway, Dr. Epstein said.

"One could conceptualize this as at least three functions, as being a resistor, a filter, and involved in immune surveillance," he added.

Several new theories have emerged from this intensified study.

"The first new idea is that the outflow pathway cells are not static. They are constantly changing their shape, changing their attachments, in fact moving around," Dr. Epstein said. "Glaucoma is a loss of dynamic function, and this is why the static histopathology of POAG is frankly so boring and uninformative."

Loss of dynamic function The loss of dynamic function in glaucoma is the converse of the cytoskeletal drug work that many investigators are performing to develop specific treatments for the outflow pathways, Dr. Epstein said. "Very simply, if one has cells from the trabecular meshwork that change their shape, one can open up spaces for fluid flow, including through the inner wall of Schlemm's canal."

An important corollary to this dynamic hypothesis is that all of the current glaucoma therapies that are nonspecific need to be retargeted to focus on the trabecular meshwork and re-establish normal dynamic function, he added.

"Many have shown that with rising pressure in the eye, the cells stretch, and we would hypothesize that this results in the release of permeability factors that act to increase outflow," Dr. Epstein said. "In fact, in various preparations, when one raises the pressure, all kinds of new gene products occur. So POAG would be a defect in either the release or synthesis of permeability factors or a lack of downstream responsiveness in the distal outflow pathway."

Genetic, environmental factors Dr. Epstein also addressed one of the biggest mysteries in POAG, which is why the disease is delayed for decades, especially if it has a genetic component.

"The answer may be that it requires a genetic predisposition but a lifetime of environmental cellular stress along the outflow pathway," he suggested.

This theory also leads to the question of why cell death occurs in the outflow pathway in POAG. Dr. Epstein discussed what he termed a "proteasome hypothesis," first proposed by Pedro Gonzalez, PhD, explaining that every cell in the body is constantly making and breaking down proteins as part of the dynamic modulation of cell function rather than as an end-stage waste product. The cell organelle involved in this breakdown is the proteasome. With age and disease, the proteasome loses its ability to accomplish the breakdown rapidly, and misfolded protein accumulates inside the cell and also extracellularly.