RGC replacement one step closer to reality

Progress occurring on several fronts is creating optimism that retinal ganglion cell (RGC) replacement may become a reality for preserving or restoring vision in patients with glaucoma, according to Jeffrey L. Goldberg, MD, PhD.

"All available medical and surgical treatments for glaucoma target IOP, but while IOP is a risk factor for glaucoma, the underlying disease is an optic neuropathy characterized by loss of RGCs," said Dr. Goldberg, professor and chairman, Byers Eye Institute, Stanford University, Palo Alto, CA.

"The real hope for advancing glaucoma care in the future is to discover therapies that target the RGCs to stave off or even restore the vision loss that can be so profound with this disease," Dr. Goldberg said. "We have encouraging evidence supporting the potential for RGC therapies, but there are many questions yet to be answered and much work needs to be done."

Important advances are occurring both in basic research and in clinical trials.

Among the developments taking place in the laboratory, there has been progress delineating molecular pathways for generating RGC-like cells from human stem cells.

Dr. Goldberg noted that results from previous research in animal models demonstrated that RGC cells delivered into the vitreous migrated to and integrated into the retina and then grew lengthy axons projecting down the optic nerve and extending to the brain.

However, a low rate of RGC differentiation from progenitor or stem cells in vitro limited further development of RGC cell therapy.

"The signaling pathways that make photoreceptors out of stem cells or retinal progenitor cells have been understood for a long time, but it has been more challenging to define the pathway for specifying RGC fate," Dr. Goldberg said.

To solve this problem, Dr. Goldberg and colleagues undertook a screen of developmentally expressed transcription factors.

In their work, they discovered that a molecular pathway involving Sox4/Sox11 was required for RGC differentiation and optic nerve formation in mice in vivo and was sufficient for promoting differentiation of human induced pluripotent cells and human embryonic stem cells into RGC-like cells in culture [Chang KC, et al. J Neurosci. 2017;37:4967-4981].

"The induced cells are structurally and functionally similar to endogenous RGCs," Dr. Goldberg said. "Not only do they look like RGCs and express protein markers typically expressed by the RGCs, but they also mimic RGCs in terms of electrophysiologic activity."

Research developing new biomarkers as study endpoints is also progressing and is important and exciting because of its implications for facilitating the process of candidate discovery and decreasing the time needed to demonstrate efficacy.

"By using these biomarkers, we can test new candidates for neuroprotection and vision restoration in a shorter time frame, and that should help us to accelerate investigations towards finding new treatments for glaucoma," Dr. Goldberg said.

The new biomarkers include new imaging modalities being developed in the laboratory of Alfredo Dubra, PhD, associate professor of ophthalmology, Stanford University School of Medicine.

"Dr. Dubra and colleagues are creating new adaptive optics-based imaging modalities that are providing very high-resolution measurements of RGCs, their axons, and even the subcellular elements inside the axons that we think will give us insight on the mitochondrial health of the cells," Dr. Goldberg said.

"With this noninvasive modality, we will be able to determine with confidence whether investigational agents are having biologic effects in early phase clinical testing," Dr. Goldberg said.

Clinical trials under way

Promising candidates for neuroprotection in glaucoma that target RGC viability are being investigated in clinical trials. Two studies are under way at Stanford University, and Dr. Goldberg is the principal investigator for the trials.

Topical treatment with recombinant human nerve growth factor (Dompé Farmaceutici) is being evaluated in a phase I single center, double-masked, placebo-controlled study is being conducted at Stanford and includes 60 patients with primary open-angle glaucoma. Eligible patients had progressive disease despite maximal therapy or stable IOP but diminished vision. The trial has a 32-week duration.

Stanford is also participating in a phase II multicenter, single-masked randomized trial of NT-501 encapsulated cell therapy (Neurotech), an intravitreal device that secretes ciliary neurotrophic factor (CNTF). Other participating sites are Glaucoma Associates of Texas, Dallas, Columbia University, New York, and New York University, New York.

Enrolled patients received NT-501 or underwent sham surgery. The primary outcome analysis will be performed at 6 months and follow-up will continue to 2 years.

Disclosures:

Jeffrey L. Goldberg, MD, PhD
E: jlgoldbe@stanford.edu
This article was adapted from Dr. Goldberg's presentation during Glaucoma Subspecialty Day at the 2017 meeting of the American Academy of Ophthalmology. Dr. Goldberg has no financial interests in the products discussed.