Restoring Optic Nerve Health

New neuroprotection and neuroregeneration strategies for glaucoma now entering clinical trials. Roibeárd O’hÉineacháin reports from the ninth World Glaucoma E-Congress

Several promising new approaches to neuroprotection in glaucoma patients are now in preclinical and clinical trials, bringing them a step closer from the laboratory to the patient, Jeffrey Goldberg MD, PhD told the virtual meeting.

Professor Goldberg noted the fundamental problem underlying irreversible vision loss in glaucoma is retinal ganglion cells do not regenerate after optic nerve injury but instead undergo a retrograde degeneration of their axons, ultimately leading to cell death. However, there is this window between retina ganglion cell injury and death where therapeutic intervention might protect the cells and promote axon regeneration down the optic nerve and dendrite regrowth into the retina.

Therapeutic candidates for neuroprotection include neurotrophic factors that could prevent RGC apoptosis, blocking the complement protein C1q, or enhancing insulin or insulin-like growth factor signalling. Another potential new strategy is to target the enzymes that mediate axon regenerative failure, like Rhokinase (ROCK), for which there are now commercially available Rho-kinase inhibitors.

There are now several trials using these approaches in various stages. One recently completed trial tested topically applied nerve growth factor, while another recently completed trial involving intravitreal injection of a C1q-blocker showed a great reduction in C1q levels in the eye. There is also a phase-two randomised controlled trial currently underway testing ciliary neurotrophic factor, which research has shown to prevent the death of retinal ganglion cells and promote regeneration of their dendrites and axons.

In addition, Prof Goldberg noted studies conducted by several research groups demonstrated very clearly over the years that ROCK-inhibitors promote cell survival and regeneration. For example, in a recently published study he and his associates conducted, topical netarsudil promoted survival and RGC regeneration and strongly promoted axon regeneration down the optic nerve in a rodent model of glaucoma.

Prof Goldberg noted that in the past, conducting neurotrophic trials was a daunting prospect because of the disease’s slow progress. It was also assumed necessary to have large study populations with a long follow-up to show a treatment effect. However, new emerging trial designs allow primary neuroprotection endpoints that can be measured in a year or a year-and-a-half with hundreds rather than thousands of patients.

“What we’ve learned is that neurotrophic factors, Rho-kinase inhibition, and other strong candidates are ready for neuroprotection testing in glaucoma, that these therapeutic candidates can be studied in our glaucoma patients, and that merging neuroprotection testing with biomarker exploratory endpoints to crossvalidate are going to give us particular power as we launch these trials,” Prof Goldberg concluded.

Jeffrey Goldberg MD, PhD is Professor and Chair of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA.

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