Neuroregeneration Research Promising for Glaucoma

Laird Harrison

March 02, 2015

CORONADO, California — Techniques for regenerating neurons damaged by glaucoma, which have had good results in animals, have improved vision in humans in a small preliminary trial.

"We've made a lot of progress," said Jeffrey Goldberg, MD, from the University of California at San Diego.

No matter what causes the initial injury to retinal ganglion cells, they can't regenerate on their own, he explained. However, "there may be a window of opportunity to heal these cells before they die."

The results of the trial and other advances in neuroregeneration research were presented during a joint symposium of the American Glaucoma Society 2015 Annual Meeting and the North American Neuro-Ophthalmology Society.

Dr Goldberg and others have been exploring ways to stimulate growth in retinal ganglion cells in animals. These include using neurotrophic factors to stimulate regeneration in injured retinal ganglion cells.

And with a kind of gene therapy that blocks factors that limit growth, researchers have achieved long-distance regeneration down the optic nerve, Dr Goldberg reported. "We're making a lot of progress getting axons to regenerate back to the brain."

Researchers are also using stem cells to make neurotrophic factors or to replace retinal ganglion cells. Creating new retinal ganglion cells out of stem cells is challenging because the cells must grow dendrites into the inner plexiform layer and axons back to the brain, he said.

After retinal ganglion cells were transplanted from one healthy animal to another, some grew axons to the brain. However, it is not clear how well this approach will work in animals with damaged neurons.

From Lab to Clinic

Dr Goldberg's team was looking to move this research into the clinic. "With that in mind, a few of us started two phase 1 clinical trials," he said.

In one of the single-center investigator-initiated nonmasked trials, 11 patients were treated with a ciliary neurotrophic factor implant (NT-501, Neurotech) for glaucoma (NCT01408472). All experienced progression despite a maximally tolerated reduction in intraocular pressure, or were stable but had significant visual field loss. The fellow eye was used as the control.

In the other trial, 11 patients were treated with the implant for nonarteritic ischemic optic neuropathy (NCT01411657).

The researchers are still analyzing data, but they have made more progress on the glaucoma study. Dr Goldberg gave an overview of the preliminary results.

The NT-501 implant is loaded with human retinal pigment epithelial cells. It secretes about 20 ng/day of ciliary neurotrophic factor for years, if not indefinitely. The implant is inserted through the pars plana and secured to the scleral closure.

At 18-month follow-up, intraocular pressure was equally well controlled in treated and untreated eyes.

The visual field index of the untreated eye decayed slightly over the 18 months, but the implanted eye showed about a 10-point increase. In addition, contrast sensitivity was stable in the implanted eye but declined slightly in the fellow eye.

The nerve fiber layer and the macular ganglion complex thickened in the treated eye in eight or nine of the patients, whereas they were stable in the fellow eye. The change was detectable as early as 1 month after implantation.

"We don't actually know if it's an improvement, because we've never had a treatment that thickened the nerve fiber layer before," cautioned Dr Goldberg. "We know a thinning nerve fiber layer is probably a bad thing, but these are early days for these kinds of patients."

Such findings are becoming increasingly important as researchers identify more and more similarities between glaucoma and other neurologic diseases, said session moderator Helen Danesh-Meyer, MD, from the University of Auckland in New Zealand.

Glaucoma as a Neurodegenerative Disease

On one hand, glaucoma progresses like a neurodegenerative disease, she explained. And it's more prevalent in people with neurodegenerative diseases, such as Alzheimer's. In addition, the accumulations of proteins and neuroinflammation in glaucoma resemble processes seen in some other neurodegenerative diseases, said Dr Danesh-Meyer.

On the other hand, certain biomechanical factors seem to separate glaucoma from other neurodegenerative diseases, she explained. Intraocular pressure is the most obvious of these. And unlike other neurodegenerative diseases, glaucoma starts with a specific point of injury, she pointed out. In addition, in Parkinson's disease, some cells are always spared, but this is not true in glaucoma.

Dr Danesh-Meyer pointed out that some neurodegenerative diseases have a prion-like quality. "They have taken Alzheimer's proteins and injected them into rodents, and 2 or 3 years later they develop Alzheimer's," she said. "We need to explore that in glaucoma."

All these differences and similarities leave many open questions about the neurology of glaucoma, she added.

Dr Goldberg reports relationships with Alcon, Allergan, Emmetrope, Annexon, KLFs, Janssen, Theravance, and Novoron, but none relevant to this presentation. Dr Danesh-Meyer has disclosed no relevant financial relationships.

American Glaucoma Society (AGS) 2015 Annual Meeting and North American Neuro-Ophthalmology Society (NANOS). Presented February 27, 2015.

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