New agents and devices offer promise to control IOP and slow, perhaps even stop, the advancing vision loss that is common in glaucoma. Research and development to restore vision is starting to show significant results in preclinical models and early stage clinical trials.
Growing numbers of new agents and devices promise to help clinicians better control intraocular pressure (IOP) and slow, perhaps even stop, the advancing vision loss that is so common in glaucoma. Research and development in techniques to restore vision remain at earlier stages.
“There are about 6 million people worldwide estimated to be blind from glaucoma,” said L. Jay Katz, MD, director of the Glaucoma Service, Wills Eye Institute, and professor of ophthalmology, Jefferson Medical College, Philadelphia. “Some of that may be from lack of care or noncompliance, but there are good studies showing that despite good medical care, vigilant medical care, 15% to 20% of patients may lose vision in one or both eyes during the course of care for glaucoma. There is an enormous unmet need in restoring their sight.”
Restoring sight was the focus of “New Horizons in Glaucoma Treatment: From Vision Restoration to Optic Nerve Regeneration” at the 2016 Glaucoma 360 meeting. There have been brief glimpses of vision loss reversal, said Dr. Katz, who moderated the session, but vision restoration research is starting to show significant results in preclinical models and early stage clinical trials.
It was long believed that damaged optic nerves were incapable of regeneration, but researchers have recognized that optic nerve damage is not always permanent. The question is how best to stimulate regeneration.
Ocular injuries that stimulate inflammation also stimulate production of a protein called Oncomodulin (Ocm), which can induce retinal ganglial cells (RGC) to begin regenerating axons damaged by injury. But an oncosuppress gene, called pten, inhibits axon regeneration. Blocking pten activity in RGC releases the brakes on RGC axon growth.
“Some of these regenerating axons are homing in on the appropriate brain nuclei,” said Larry Benowitz, PhD, director, Laboratories for Neuroscience Research in Neurosurgery, Boston Children’s Hospital, and professor of neurosurgery and ophthalmology, Harvard Medical School, Boston. “They are probably forming synapses. The bad news is that at last two-thirds of RGCs die after optic nerve injury in animal models and only about 10% of the remaining RGCs regenerate axons.”
In searching for a way to increase RGC regeneration, researchers focused on zinc. Zinc accumulates in retinal synapses after optic nerve injury, then migrates to RGCs. Removing zinc by chelation promotes both RGC survival and axon regeneration.
“If we combine zinc chelation with pten deletion, we can get some axons to regenerate the entire length of the optic nerve,” Dr. Benowitz reported. “While we have not yet studied this activity extensively in glaucoma, we can get about half of the RGCs surviving for months after injury.”
Stem cell therapy
The National Eye Institute (NEI) has a simple goal: to regenerate neurons and neural connections in the eye and visual system. Research teams are focusing on photoreceptor loss, ganglion cell injury, and optic nerve regeneration using induced pluripotent stem cells (iPS).
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“For all practical purposes, iPS are the equivalent of embryonic stem cells, but we can make them from any adult,” said Kapil Bharti, PhD, Stadtman Investigator at the NEI’s Unit of Ocular Stem Cell & Translational Research. “We can take 20 mL of your blood and reprogram it to become iPS, hence no political issues. The other advantage is that these cells are personalized. We can make cell therapy for one single patient.”
NEI researchers are developing a three-dimensional model of the back of the eye for in vitro-disease modeling, drug testing, and cell therapy to restore vision. The initial project is focused on age-related macular degeneration (AMD), Dr. Bharti said, but the same platform should be translatable to glaucoma and other visual diseases.
In AMD, retinal pigment epithelial (RPE) cell atrophy leads to the death of photoreceptor cells and impaired vision. Using bioprinting and tissue-engineering techniques, the team has created an iPS-derived RPE patch. The system has been scaled up to a five-month, GMP-manufacturing process capable of producing clinical product, an implantable RPE patch that can be implanted. Human RPE patches have been successfully implanted in pigs to treat laser-induced RPE ablation.
“We hope to start a clinical trial in 2018 using autologous patches in AMD,” Dr. Bharti said. “This same manufacturing process will leverage many more clinical investigation in other iPS cell types.”
The eye is a key element in vision, but it is not the only element. Neural signals generated by the eye are transmitted to the brain, processed, and translated into vision.
“The brain deserves a better reputation in ophthalmology,” said Bernhard A. Sabel, PhD, director of the Institute of Medical Psychology, Otto von Guericke University of Magdeburg, Germany. “Because we are so eye-focused, we don’t very often think of what lies behind the eye, the brain, and the role it plays in vision.”
Damage from glaucoma and other visual diseases is seldom complete, he continued. Most patients show residual vision, areas of good function, partial function, and no function. Just as physical therapy exploits neural plasticity to improve residual function following stroke or other injury, he exploits neural plasticity to improve residual vision.
In normal vision, the brain amplifies and processes retinal signals to produce vision. Electroencephalograms show that normal visual-processing networks are disrupted in blind individuals. Specific frequencies of alternating current stimulation to the eye and the brain for 20 to 40 minutes daily over 10 days or longer can induce the brain to create alternate processing pathways and improve vision impaired by glaucoma.
Early stage clinical trials showed a 24% improvement in visual field and 60% improvement to impaired visual field sectors. About a third of patients were non-responders, while 70% reported subjective improvement to their vision. A few patients reported mild headache and there were no serious adverse events.
Dr. Sabel noted that electrical stimulation is not currently reimbursed by national health plans, but some commercial plans cover treatment.
Multiple studies have shown that different types of electrical stimulation to the optic nerve can induce structural and functional restoration after the nerve has been crushed or transected. The idea of using electrical stimulation to restore vision is not new.
Charles Le Roy used static electricity to induce phosphenes, a perception of light, in 1755. Over 250 years later, EBS Technologies is using electrical stimulation to improve vision and quality of life for patients with optic neuropathies.
The goggle-like device delivers electrostimulation above and within the orbital space for both eyes. The intensity of the stimulus is adjusted to produce phosphenes in the absence of light.
EBS has treated about 160 patients in randomized controlled trials, said Jens Ellrich, MD, PhD, chief medical officer, mostly with glaucoma. The company was granted a CE mark in 2013 and has opened five treatment centers. Follow-up has shown an improvement of vision that persists for at least nine months as well as improvements in quality of life.
“We see a significant decrease in visual defects after about 3 months of treatment,” he said. “Axonal regeneration and improvement in RGCs is not a process that happens in a few days, but takes several weeks.”
It may also be possible to improve vision using drug-based techniques. Neurotech Pharmaceuticals is developing an encapsulated cell therapy device that can produce clinically relevant quantities of therapeutic proteins in the eye.
“The effects of ciliary neutrophilic factor (CNTF) in preserving the viability of at-risk RGCs has been well established in multiple ex vivo and in vivo models,” said Charles Johnson, MD, chief medical officer. “The question is how you use it. CNTF has a half-life of less than three minutes, so using it as an injectable is clearly impractical.”
Neurotech’s solution was a propriety cell line derived from human retinal pigment epithelial cells. Cells are transected with CNTF or some other useful protein and encapsulated in a semipermeable membrane that allows ingress of oxygen and nutrients with egress of therapeutic protein. The capsule is attached to the scleral wall using a titanium suture clip.
Phase I trials in 11 glaucoma patients show statistically and clinically significant improvements in vision in the treated eye versus untreated eyes in the same patients. Implants secrete about 20 ng of CNTF daily. Improvement in visual field and contrast sensitivity can be seen within a month and persist at least 18 months.
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“We have an apparent improvement in visual field and contrast sensitivity,” Dr. Johnson said. “We are moving forward with randomized controlled trials. The neuroenhancement signal, if it is replicable, will be seen within six months. We plan to initiate those trials the first half of this year.”