New measure of cell metabolism may speed progress of therapies

Research into biomarkers for glaucoma is starting to raise hope for new therapies, according to Jeffrey L. Goldberg, MD, PhD.

“We’re turning to the therapeutic side, sort of addressing the stem-cell side,” said Dr. Goldberg, professor and chairman, Byers Eye Institute, Stanford University, Stanford, CA.

In a phase I trial, 11 eyes receiving ciliary neurotrophic factor scored more highly on visual field index and in the retinal nerve fiber layer thickness than untreated fellow eyes, said Dr. Goldberg at the 6th annual Glaucoma 360 New Horizons meeting.

Dr. Goldberg and his team implanted the NT-501 (Neurotech)-containing retinal pigment epithelium cells in a semipermeable membrane-into the patients. Inserted through the pars plana and secured to the sclera closure, the implant secretes about 20 ng per day of ciliary neurotrophic factor.

He cautioned that the study was only designed to measure safety so “we couldn’t do statistics” regarding efficacy. However, there were no effects on IOP or other adverse events.

The team is working to recruit patients for a second phase of the trial in which patients will be randomly assigned 1:1 to sham surgery or implant, with an opportunity to cross over to implants in an open-label extension.

Their goal is to show improvement in dysfunctional, but not yet dead, retinal ganglion cells.

“In my laboratory, we’re very focused on neuroprotection, regeneration, and neuro-enhancement,” he said.

The first results are expected this year.

The approach rose out of research into biomarkers as part of the Biomarker Initiative of the Glaucoma Research Foundation’s Catalyst for a Cure project whose principle investigators are Dr. Goldberg, a neuroscientist; Alf Dubra, PhD, an optical engineer at Stanford University; Andy Huberman, PhD, a neuroscientist at Stanford University, and Vivek Srinivasan, PhD, an applied physicist and optical engineer at the University of California, Davis.

“Coincidentally, we have all converged in the (San Francisco) Bay Area,” Dr. Goldberg said.

The project began with fundamental questions about how to diagnose glaucoma and test the efficacy of new therapies.

IOP rises early in the glaucoma disease process, but Dr. Goldberg and his colleagues are focused on what happens next-axon transport failure, axon damage, and especially the eventual death of retinal ganglion cells (RGCs).

An early insight of the biomarker project was that “off” RGC dendrites (which fire when the light is off) decay before “on” RGC dendrites (which decay when light is on.) The hope is to design a new visual field exam that measures “off” RGCs separately.

The project has been able to image the cells anatomy and the researchers are exploring the metabolic process of these cells to learn more about what causes the damage.

They have found that mitochondria in RGCs fragment and stop moving early in glaucoma. They are using visible-light OCT to map microvascular flow, oxygenation, and hematrocrit concurrently.

But in animal models they have also found signs that transplanted RGCs respond to light stimulation, sending axons across the optic chasm to appropriate targets in the brain

Since many outcomes in glaucoma take a long time to develop, the hope is their new tools for measuring cell metabolism can speed the progress of therapies.