RCG REGENERATION

Glaucoma treatment strategies are starting to shift from only treating increased intraocular pressure (IOP), to treating the underlying damage to the retina and optic nerve. Current efforts to stimulate retinal ganglion cell regeneration were described by Jeffrey L Goldberg MD, PhD, professor and director of research, Shiley Eye Center, UCSD, San Diego, US, at the World Ophthalmology Congress in Tokyo.

“While we now mostly focus on controlling the pressure in the front of the eye, the damage is happening in the back of the eye. The fundamental problem we have with vision loss and vision restoration in glaucoma is that there is no retinal ganglion cell regeneration after optic nerve injury. The cells die and there is no endogenous replacement,” he noted.

Researchers are looking at treatment strategies that might approach retinal ganglion cell loss at different stages in the disease process. Intervention during the early stages of disease would attempt to keep existing retinal ganglion cells alive through the use of neuroprotective agents. A related approach would involve introducing neurotrophic factors and growth factors that could help the cells regenerate.

The most recently tested approach involves introducing one such factor, ciliary neurotrophic factor (CNTF) in an attempt to promote both retinal ganglion cell survival and optic nerve regeneration. Studies have recently been conducted in patients with glaucoma, as well as with retinitis pigmentosa, macular telangiectasia and geographic atrophy.

In a previous multicentre Phase II study, patients with advanced geographic atrophy associated with non-neovascular age-related macular degeneration showed promising results on visual acuity when treated with CNTF in a proprietary approach known as encapsulated cell therapy (NT-501, Neurotech). This involves implanting eyes with a small immunologically neutral capsule designed to release CNTF. The 1.0 x 6.0mm implant contains an RPE-derived cell line engineered to continuously produce CNTF for extended periods in humans. It is a relatively simple surgical procedure, implanting the device at the pars plana via a small incision and securing it with a single suture. It is placed outside of the main visual axis.

That study confirmed the utility of the implant for safe, long-term delivery of biological agents. While no improvement in visual acuity was noted, there was a trend towards visual stabilisation which was statistically significant among patients with better vision at baseline. Investigators also reported a dose-dependent, statistically significant increase in retinal thickness
as measured by optical coherence tomography (OCT).

Dr Goldberg presented early results from the first clinical trial to use CNTF in patients with glaucoma. One of two open-label studies he conducted enrolled eleven patients with primary open-angle glaucoma (POAG) starting in February 2012; the second study enrolled patients with non-arteritic ischaemic optic neuropathy, but the results are not yet available. For inclusion in the study patients were required to have clinical evidence of progressive retinal ganglion cell dysfunction demonstrated by functional and structural testing. Patients also had to have failed maximal IOP-lowering therapy, or have visual defects affecting quality of life.

No serious adverse events

All patients completed the study. There were no surgery or implant-related serious adverse events. Patients did experience minor postoperative events including irritation and redness which resolved in the first month. There were also reports of anisocoria associated with the implant that has previously been described with CNTF and is known to be reversible.

“Early conclusions from current research suggest that CNTF appears to be safe in humans. There was also some indication of biological effect with a marked increase in the retinal nerve fibre layer demonstrated by both OCT and GDX.”

The approaches now being investigated reflect an improved understanding of the underlying pathology of glaucoma. The first step is characterised by axon transport failure following increased IOP. The resulting axonal damage manifests as axonal thinning and dendritic changes leading to retinal ganglion cell death later in the process.

CNTF is a member of the IL-6 cytokine category. It is released by retinal glial cells in response to injury. Many years of laboratory research have shown that CNTF promotes retinal ganglion cell survival, protects retinal ganglion cells from degeneration and promotes optic nerve regeneration.

Dr Goldberg also reported promising animal studies in which implanted retinal ganglion cells showed evidence of growing both dendrites into the retina and axons along the retinal nerve fibre layer and across the optic chiasm. This suggests that it may be possible to transplant RGC cells even in the very late stages of glaucoma, he said.

Implantable devices for sustained drug delivery are becoming a new wave of treatments for eye disease. Neurotech, the company that makes the NT-501 CNTF implant is also developing another product, NT-503, that is being evaluated for intraocular delivery of a VEGF receptor fusion protein for treatment of macular disease. A Phase II study in wet AMD is under way that shows control of macular oedema for at least 12 months.

A Genentech scientist also reported at the conference that his company is developing an implant for slow release of anti-VEGF therapy.