Catalyst for a Cure team establishes targets for glaucoma biomarkers

The four principal investigators of the Catalyst for a Cure Biomarker Initiative-Alfredo Dubra, PhD; Jeffrey Goldberg, MD, PhD; Andrew D. Huberman, PhD; and Vivek J. Srinivasan, PhD-outline the details behind their research. (Video courtesy of Glaucoma Research Foundation)

San Francisco-Several years ago, the Glaucoma Research Foundation (GRF) expanded its initiative to advance glaucoma research through a collaborative approach by creating a second Catalyst for a Cure research team.

The new group was charged with finding biomarkers for the earliest pathologic events in glaucoma onset and progression. At the Glaucoma 360 Annual Gala last night, the four principal scientists in the Catalyst for Cure Biomarker Initiative updated attendees on their progress.

The principal investigators of the consortium are:

• Alfredo Dubra, PhD, assistant professor and co-director, Advanced Ocular Imaging Program, Eye Institute, Department of Ophthalmology, Medical College of Wisconsin, Milwaukee.

• Jeffrey Goldberg, MD, PhD, professor of ophthalmology and director of research, Shiley Eye Center, University of California, San Diego.

• Andrew D. Huberman, PhD, assistant professor of neurosciences, neurobiology, and ophthalmology, Shiley Eye Center, University of California, San Diego.

• Vivek J. Srinivasan, PhD, assistant professor of biomedical engineering, University of California, Davis.

The consortium of research labs has identified a series of targets for glaucoma biomarkers. In addition, the group has built a series of novel instruments for imaging the retina noninvasively. The instruments will be used to measure and test the new biomarker targets.

The labs are highly collaborative, combining expertise in state-of-the-art imaging, cellular and molecular biology, and clinical glaucoma, applying their expertise toward biomarker discovery. The direct goal of the group is to improve patient care.

The major highlights of the group’s research efforts include:

• Identification of a subset of retinal ganglion cells (RGCs) that are among the earliest to show changes in glaucoma, called “Off cells.” This discovery has generated a new approach to designing specific vision tests for identifying early glaucoma and/or progression in patients whose condition will get much worse if left untreated. The team also is developing tools to image the blood supply to the Off cells, as well as their energy or oxygen consumption, using custom imaging technologies.

• The degeneration of the connections, or “synapses,” between RGCs and their “neighbors” is an early event in glaucoma. The team is developing probes for synaptic labelling to be perfected in animal models before moving to human testing. The group is also developing imaging technology to view the synapses in the living eye.

• The smallest retinal blood vessels are intimately involved with RGCs in the retina and optic nerve. The team has developed a number of novel approaches to visualize the microvasculature noninvasively, measure local blood flow and oxygenation (including to the Off cells), and even develop new probes that could be given as a simple blood test to determine whether retinal neurons or axons going into the optic nerve are dysfunctional or at risk of death.

• The energy sources of the cell, mitochondria, are dysfunctional in both form and function in glaucoma models. The team has made significant progress in using noninvasive imaging modalities to detect fluorescently labeled mitochondria in animal models. The team has characterized the relationship between RGC mitochondria and activity in normal versus glaucomatous eyes.

• In addition to progress made in the biology of glaucomatous RGC degeneration, the team has made considerable advances in noninvasive, retinal-imaging instruments, including animal and human adaptive optics-scanning laser ophthalmoscopes; visible light, path-length-resolved spectroscopy; and infrared OCT angiography.

The Catalyst for a Cure team has developed the translational pipeline to reap the biomarker discovery benefits of these tools over the coming years. Together, one or more of these approaches may yield highly sensitive biomarkers for glaucoma detection and progression, and provide a sensitive means to monitor treatment efficacy.

The team will continue to work toward validation of these targets and technologies in animals, and toward a rapid translation into human testing.

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