Glaucoma cure may be found in newly discovered biomarkers

San Francisco-The study of biomarkers for glaucoma is pointing to promising avenues for new treatments, according to Vivek J. Srinivasan, PhD. 

As part of their work for the Catalyst for a Cure Biomarker Initiative of the Glaucoma Research Foundation, Dr. Srinivasan and three other scientists have identified early warning signs that might allow them to intervene before vision loss occurs, and experimented with ways of regenerating ganglion retinal cells.

2016 Catalyst for a Cure Progress Report from Glaucoma Research on Vimeo.

Dr. Srinivasan outlined this work here at the foundation’s Glaucoma 360 New Horizons Forum.

Dr. Srinivasan with Glaucoma Research Foundation President Thomas M. Brunner

 “Our approach was to draw from the basic biology and use engineering to develop new tools to visualize these biomarkers, then use our clinical expertise to determine how best to use these to help patients in the clinic,” he said.

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In addition to Dr. Srinivasan, an assistant professor of bioengineering at the University of California, Davis, the team includes :

• Andy Huberman, PhD, of the University of California, San Diego, an expert in the visual system and how it changes;

• Jeffrey Goldberg, MD, PhD, of Stanford University, a glaucoma specialist and retinal ganglion expert; and

• Alfredo Dubra, PhD, of the Medical College of Wisconsin, another biomedical engineer.

The team’s point of departure is that glaucoma occurs as a result of the dysfunction of retinal ganglion cells.

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“The real question for us is how do we measure this accurately and distinguish dysfunction from death, or dysfunction at a point where it’s treatable,” Dr. Srinivasan said.

Insufficient risk factors

Risk factors, such as IOP, are not sufficient for diagnosing the disease or measuring its progress, he said.

For that, clinicians need biomarkers-measurable characteristics of a disease that reflect its presence, severity or response to treatment.

Courtesy of Glaucoma Research Foundation.One biomarker in glaucoma is a functional test from a visual field, but this measures only gradual progression of the disease, he said.

Likewise, fundus photographs can track fairly small changes in the optic nerve head. However, these low-resolution images do not show early or subtle disease progression, Dr. Srinivasan said.

Optical coherence tomography provides a usefully quantitative number that can be followed over time. But the changes it detects take place only after nerve fiber axons are lost.

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Instead, Dr. Srinivasan and his colleagues are searching for ways to detect changes in nerve cells and protect them before patients lose vision.

“To do this, and to evaluate neuroprotectants, we need biomarkers that allow us to measure these changes in a short timeframe,” he said.

As a step in that direction, Dr. Huberman’s lab developed genetic tools to label retinal ganglion signaling, observing how these cells turn on or off in response to light.

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“He has followed these types of cells and characterized in painstaking ways how they change in early glaucoma,” Dr. Srinivasan said.

“What Andy found is that not necessarily a specific cell type, but in a specific layer in the retina, ganglion cells showed early dendritic changes before the other hallmarks of disease were evident,” he said.

More about the "off" layer

The researchers are referring to this as the “off” layer. The layer is also a site rich in blood vessels and higher energy usage.

This is leading toward a new type of visual field test that uses light stimuli designed to target the “off” pathway.

Other imaging biomarkers that apply to this layer are visualization of blood vessel cells’ response to glaucoma and of the ganglion cells’ energy usage as well as their connections, Dr. Srinivasan said.

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The layer where Dr. Huberman identified changes indicative of glaucoma is in the intermediate layer of the three-tiered vasculature system of the retina. The team is trying to determine whether vasculature is correlated with the changes in the dendrites Dr. Huberman has observed.

At the same time, the team is looking for contrast agents that can image the vasculature with improved resolution of capillaries.

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The team is also using optical coherence tomography with shorter wave-lengths to make this imaging modality more sensitive to functional contrast and oxygenation changes.

Dr. Dubra’s lab is testing adaptive optics, a technique used for the Hubble Space Telescope, to correct for aberrations allowing better images of the back of the eye. This approach has allowed Dr. Dubra to visualize individual capillaries not seen in conventional optical coherence tomography angiography.

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Dr. Huberman is also looking at ways to stimulate independent growth pathways in ganglion cells, Dr. Srinivasan said. In early experiments using visual stimulation and mTOR signalling, he has seen regeneration of axons back toward their targets in the brain.

After successful experiments in animal models, the biomarkers team is trying these approaches in healthy human subjects, and hoping to soon validate them in glaucoma suspects and patients, Dr. Srinivasan said.