Jeffrey L. Goldberg, MD, PhD

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	Take-home message: Findings from basic science research elucidating the mechanisms of retinal ganglion cell axon degeneration, regeneration, and death have identified new therapeutic targets for glaucoma that are being investigated in preclinical and clinical studies.

	By Cheryl Guttman Krader; Reviewed by Jeffrey L. Goldberg, MD, PhD

-Growing understanding of the pathophysiology of glaucoma is opening the way to the development of strategies for neuroprotection, neuroregeneration, and neuroenhancement.

	While the research is still at an early stage, the progress being made is encouraging, according to Jeffrey L. Goldberg, MD, PhD.

	“Based on animal models, we have every reason to think that retinal ganglion cell (RGC) death occurs as a relatively late event in glaucoma pathophysiology, and that points to a window of opportunity for interventions to protect the RGCs, enhance their function, or enhance regrowth of their axons to targets in the brain,” said Dr. Goldberg, professor of ophthalmology and chairman, Byers Eye Institute, Stanford University, Stanford, CA.

	“In humans, it will be hard to distinguish whether a particular modality is providing neuroprotection, neuroenhancement, or neuroregeneration,” he said. “However, a treatment with any of these activities would be a major step forward.”

	Regenerative strategies aim to overcome the fact that once the axon of a RGC is injured in the optic nerve, it does not regrow to re-establish the connection between the eye and the brain. Based on understanding of the molecular basis for why RGC axons stop growing and of the genes involved, various strategies have been tested in animal models with promising results. Those studies have been conducted with agents that block inhibitory pathways and with neurotrophic factors that might enhance intrinsic growth ability, which seems to be retained but decreases sharply around birth.

	Stem cell therapy is another active area of research. Studies investigating its application are looking at stem cells both as a source for secreting neurotrophic factors, which could enhance the survival of RGCs and promote axon growth, and as a method for replacing lost RGCs.

	Dr. Goldberg noted that success with stem cell therapy or RGC transplantation to replace lost RGCs will be more challenging than when the target is replacement of photoreceptor cells because of the anatomy-the RGCs have to grow dendrites into the inner plexiform layer and grow axons back to the brain. Nevertheless, there have been encouraging results in animal models.

	“I caution, however, that the best results were all studies in the absence of nerve injury, and achieving integration into injured tissue is likely to present greater challenges,” Dr. Goldberg said. “While there is a lot still to be learned, the outcomes to date are a step in the right direction.”

	Demonstrating success of any neuroprotective strategy that would prevent loss of vision is difficult considering that glaucoma is such a slowly progressive disease.

	However, Dr. Goldberg said it may be possible to demonstrate efficacy in a shorter time frame for compounds that would provide neuroenhancement, boosting the function of “sick” RGCs and thereby improving vision indices.

	In this area, phase I trials have been conducted investigating NT-501 Encapsulated Cell Therapy (ECT, Neurotech), an implant of encapsulated human cells genetically modified to secrete therapeutic doses of ciliary neurotrophic factor (CNTF), in patients with ischemic optic neuropathy and glaucoma.

	The glaucoma trial enrolled 11 patients whose disease was progressing despite maximally tolerated reduction of IOP or whose visual field defect was affecting fixation. They were followed for 18 months after undergoing unilateral implantation of NT-501 ECT inside the pars plana.

	Analyses of outcomes are still under way. Dr. Goldberg noted that there were no serious adverse events attributable to the implant, and nearly all adverse events were consequences of the implant procedure and resolved rapidly. Based on preliminary data from the implanted and fellow untreated eyes, the implant appeared to have biological activity, registering detectable differences in structural and functional endpoints.

	This article was adapted from Dr. Goldberg’s presentation at the 2015 meeting of the American Glaucoma Society. Dr. Goldberg has no relevant financial interests to disclose.

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Findings from basic science research elucidating the mechanisms of retinal ganglion cell axon degeneration, regeneration, and death have identified new therapeutic targets for glaucoma that are being investigated in preclinical and clinical studies.

Jeffrey L. Goldberg, MD, PhD

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