In The Great Gatsby, Jay Gatsby yearns for a distant green light illuminating the home of his unrequited love, Daisy Buchanan. The green light is a metaphor for Gatsby’s obsession with achieving the success offered by the elusive American dream. New technologies and treatments offer patients with various forms of blindness just that — visible beacons of light, signaling hope for a future with fully realized vision.
But the sea separating hopeful patients and scientists from the green beacon is as vast as that between Gatsby and Buchanan. Scientists inch closer, embarking on their own, unique routes. Researchers use bionic implants, gene therapy, and cellular regeneration to tackle a variety of disorders that result in blindness such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD).
Scientists have developed working therapies for patients along the way, including the gene therapy Luxturna, which was approved by the FDA in 2017 to treat RP, and a bionic microchip implanted on the retina that restores communication between photoreceptors and the brain called the Argus II, which was approved in 2013 by the FDA. But these therapies are far from a solution for all patients.
Luxturna only works for 5% of people with RP who carry a specific mutation in the retinoid isomerohydrolase (RPE65) gene. The Argus II requires invasive surgery, years of rehabilitation, and carries a hefty $150,000 price tag. Second Sight Medical Products discontinued the device in 2019, ultimately closing their doors and merging with the biopharmaceutical company Nano Precision Medical, which specializes in drug delivery implants. It’s unclear if or how the now defunct Second Sight Medical Products will support the abandoned 350 patients with the implant, who now face the decision to remove the device or navigate maintaining the device themselves. (Second Sight Medical Products did not respond to a request for comment.)
“Second Sight pioneered the field, and it was important, and somebody had to do it,” said Sheila Nirenberg, an optogenetics researcher at Weill Cornell Medicine and founder of Bionic Sight. “But I feel bad for the patients who are left with the [Argus II] still in their eye. That doesn’t seem good, and it doesn’t seem reasonable.”
New devices and treatments are rising from the Argus II’s ashes. Researchers are still developing promising prosthetic devices, many of which are being tested in ongoing clinical trials. In 2021, researchers from the biotech company GenSight Biologics reported using optogenetics — a form of genetic engineering that uses light to precisely regulate biomolecules — to control eye and brain cell function, partially restoring vision (1). And Nirenberg founded Bionic Sight to use artificial intelligence to finetune optogenetics in restoring vision. The strategy of each developing treatment differs, but they all share a common goal: help blind patients regain functional vision.
“It’s not about having a monopoly on something; it’s about solving a problem for people,” said Nirenberg. “I just want to make blind people see. Everything else will fall into place. Even if I can’t take them all the way, I’d like to get them as far as I can.”
Morse Code
Prosthetic devices that treat blindness, also known as bionic eyes, target two key contributors to vision: the retina and the visual cortex. The retina is a light sensitive layered membrane lining the back of the eye. The eye reflects a two-dimensional image on the retina, which transmits it to the part of the brain responsible for interpreting images, the visual cortex, through a series of specific electrical pulses in the optic nerve.
“In Morse code, there is dot, dot, dot, dash, dash, dash. [Electrical pulses] are a code that represents what vision is. If I were looking at your face, my cells would be sending this Morse code signal to my brain,” said Nirenberg.
The retina is composed of several cell types, including photoreceptors and neurons. The photoreceptors are the first to receive the image. There are two types of photoreceptors in the retina: rods and cones. Cones are centrally localized on the retina and function best in lighted areas. They are most important for color vision and central vision. Rods line the outer edge of the retina, function in low light, provide black and white vision, and are critical for peripheral vision.
Photoreceptors transmit their Morse codes through bipolar cells that connect to ganglion cells. The ganglion cells receive the signals, translate them, and send the message off to the visual cortex via their long, stringy axons that extend to the optic nerve.
“My photoreceptors see your face, and the retinal circuitry converts what the photoreceptors see into this secret code because the brain needs it in that code form,” explained Nirenberg. “Your left nostril may be dot, dot, dot, dash, dash, dash, dot, dash, dot. [The retina] is sending that code in pulses to a neuron that receives it and fires those pulses.”
In most retinal disorders that cause blindness, photoreceptors die, but ganglion cells remain functional. These cells can still read and translate Morse code messages, but the photoreceptors can’t send them. RP generally results from rod cell death caused by a mutation in a rod cell-specific gene.
RP can be caused by mutations in other cells in the retina. RPE65, which is the target of the only FDA approved gene therapy for RP, is expressed in the retinal pigment epithelial cell (RPE) layer bordering the photoreceptors. This epithelial layer is a selective barrier important for photoreceptor maintenance. Mutations in RPE cells leave photoreceptors high and dry, causing them to die. While this sometimes contributes to RP, it is the primary mechanism for cone cell death in AMD.
Although photoreceptor cell death is the hallmark of RP and AMD, the two diseases differ and often require different treatment approaches. People with AMD primarily lose their cone cells, which affects their central vision. Those afflicted struggle to drive and read during the day. People with RP lose their peripheral sight and most often struggle with night vision. However, death in either photoreceptor eventually causes the death of all photoreceptors, resulting in total blindness.
The goal of therapies for treating blindness is to find new ways to deliver the coded message to the cortex via electrical stimulation of the retinal neurons or visual cortex. Unfortunately, those who were born blind will not benefit from the treatments in development because their visual cortex never developed.
Replacing the signal
The Argus II artificially replaces the photoreceptor-produced signals normally sent to the retinal ganglion (2-3). People who received the implant wear a pair of goggles with a mounted camera that relays images with the implanted device via radio waves. The device is held on the eye by a band wrapped around the outside of the eye that includes a wire that receives the signal from the goggles. The signal is processed through an electronic component covered in silicone and ultimately sent to a 60-electrode array implanted on the surface of the retina that delivers pulses of electricity to stimulate the ganglion cells.
The resulting image is not what someone with natural vision would see. The image is converted to 60 black and white pixels by a video processing unit carried on the hip; healthy natural eyes can reach a 576-megapixel resolution. Argus II users see blurry, indistinct balls of light. Users must undergo extensive training to learn how to interpret the blurry images, and in the end, it generally provides them enough vision to navigate their surroundings.
Gislin Dagnelie, an ophthalmology researcher at Johns Hopkins University, helped conduct foundational experiments leading to the Argus II’s development. His team discovered that when a jolt of electricity was delivered to the eyes of a patient with RP-induced blindness, they would see a flash of light. They reported their findings in Ophthalmology in 1996 (4).
“Nine out of ten people who knew anything about how the retina works were telling the people doing these experiments, ‘you’re crazy,’” said Dagnelie.
Dagnelie calls his team stubborn, but not crazy. They tested five patients with RP and AMD and found that all patients saw a flash of light when the retina was electrically stimulated with an electrode. They added more and more electrodes and found that with two electrodes, patients saw two dots of light. And if they stimulated the retina with a row of electrodes, the patients saw a line.
“[We wondered] what it would be like if there was a whole series of dots. How many dots would make the image understandable? And what would happen if the dots became very blurry and started overlapping? Would someone still be able to understand the image?” Dagnelie remembered.
Researchers at Second Sight Medical Products developed a 16-electrode array, the very first iteration of the Argus, and implanted it into six patients. The patients saw blurry dots of light as previously reported, but couldn’t make out any detail. They created the Argus II with six rows of ten electrodes and embarked on a clinical trial. One of the sites was at Johns Hopkins University where Dagnelie worked. They tested the device in a total of thirty patients in the United States and Europe, and were excited about the results.
“They clearly saw moving shadows and very crude shapes. Some of them could learn to distinguish large letters, and they could see a strike pattern on the screen and tell whether it was horizontal, vertical, or diagonal. And they could look for a wide line on a black floor and follow it,” said Dagnelie.
It took time for patients to see these results. Since the image resolution is low, people who received the implants required extensive rehabilitation that lasted years. Now, with the Argus II discontinued and Second Sight Medical Products’ future in question, how these patients will receive support is unclear.
Dagnelie and other clinicians at Johns Hopkins University School of Medicine are helping some patients with Argus II implants. He can’t support these patients the way Second Sight Medical Products’ rehabilitation program or technical support did, but he can work to improve the device. Although the goal is to develop a device capable of producing higher resolution images, Dagnelie found a quick fix with a thermal camera. This may seem like an incremental upgrade, but for someone with minimal vision, it makes a huge difference.
“You can use a [thermal camera] to distinguish things by their temperature such as people, a hot pot of coffee, a microwave, or a heater. If someone is sitting at the breakfast table, they might want to know where their hot cup of coffee is. Or if they’re sitting at the dinner table, the warm food on their plate. Those things will stand out relative to other things around them and it will simplify the image,” said Dagnelie.
He also wants to add a depth sensor camera, which would tell the patient whether something is within arm’s reach, helping the wearer navigate obstacles as they walk. For now, he’s testing each upgraded camera separately, but combining depth with thermal sensing would strengthen the capabilities of visual prosthetics. He’s also testing if artificial intelligence can be used to help patients differentiate between objects.
Now that the Argus II is discontinued, this work may not inform future iterations of the device, but it could guide development of the next generation of prosthetics.
Upgrading the signal
Researchers developing new retinal prosthetics want to do more than upgrade the camera; they also want to improve the resolution, which requires fine-tuning the electrode array that Second Sight Medical Products initially developed.
In 2003, a group of researchers from the John A. Moran Eye Center at the University of Utah School of Medicine identified a mechanism that likely contributes to the limited resolution achieved by previous iterations of prosthetics like the Argus II. Using mouse models of RP, they discovered that the disease not only causes the loss of photoreceptors, but also that neurons in the retina form new synapses (5). Researchers validated these results in post-mortem human retinas from people with RP and AMD (6-7).
“If you’re stimulating a small group of cells, the activity is going to spread through these new connections, and that’s why things can become really blurry, particularly if you have a whole bunch of electrodes stimulating at the same time. It produces a lot of crosstalk,” said Dagnelie. “That was the first indication that made us understand why a retinal prosthesis was not going to be nearly as straightforward as we had hoped.”
Researchers at Pixium Vision claim that their prosthetic, the PRIMA System, which has the same general components as the Argus II, partially addresses this problem. The PRIMA System improves upon the Argus II design in some key ways.
The device is completely wireless. Rather than wires delivering the electrical impulse, the electrodes are activated by light. Glasses mounted with a video camera convert the observed images to near-infrared light that reflects through the eye, hitting the implanted 378 array of electrode containing pixels. The pixel array produces a pulsed electric current, communicating their electrical morse coded message to the ganglion cells.
The electrodes in the PRIMA system are placed on top of the retina, which focuses any electrical stimulation on the ganglion cells. The electrodes in the Argus II are implanted under the retina, positioning them farther from the ganglion cells. The subretinal placement of the electrodes causes them to primarily stimulate the bipolar cells.
“[Because of] where the implant sits and how it’s designed, the stimulation is very, very specific and very well localized. When you stimulate electrically with previous devices, because you were far from the [ganglion] and not in a location close to the cells, you need to shoot a lot of current. You end up stimulating a lot more cells than you need to stimulate,” said Guillaume Buc, chief technology officer at Pixium Vision.
Pixium Vision just published the results from their Phase I clinical trial testing the PRIMA System in patients with AMD (8). After receiving the implant, researchers followed patients for a year, regularly testing their vision using common visual tests such as identifying the orientation of bars and letters from the alphabet. Three of the five patients correctly identified the orientation of a line over 90% of the time following transplantation.
The researchers also determined participants’ visual acuity before and after the transplantation by asking them to read a poster with letters from 20 feet away. If someone has 20/20 vision, it means that they can read all of the letters easily from 20 feet away. 20/100 vision means that someone must be 20 feet away from an image to see it, while someone with normal vision can see it 100 feet away.
“What we see with PRIMA so far is that the restored visual sense is fine enough that patients can actually see letters and recognize letters, but not small words. It’s not like what happened with the Argus, where the patient had to scan a lot to try to understand the spatial structure of what they were looking at before they recognized the letter. It’s much more natural than that,” said Buc.
The best visual acuity patients achieved with the Argus II was 20/1260, while the PRIMA System recovered patient’s vision to 20/460, which is close to the 20/420 acuity expected from the device (9). However, the patients started off with better vision than 20/1260 already. The patient with the best visual acuity after implantation, 20/400, started with a visual acuity of 20/500.
“We need to look for technologies that allow us to get even better resolution. The one way we could do that is if instead of electrodes sitting on the surface of the retina, we had penetrating electrodes,” said Dagnelie.
Penetrating electrodes would further improve resolution by placing the electrodes closer to the targeted retinal neurons, thus requiring less stimulation.
“You wouldn’t have as much crosstalk because the crosstalk is mostly caused by the effect that we’re stimulating with much more current than we would need to if we were close to the target cells. That’s in development, but it’s in its infancy,” Dagnelie said.
Nano Retina, a biotech company developing nanotechnology-based therapeutics, is developing a retinal prosthetic with penetrating electrodes. They are currently conducting clinical trials in Europe and Israel. Five patients have already received the implant. Dagnelie is excited to see the results.
Bypassing the signal
Directly stimulating the visual cortex may bypass many of the challenges faced by retinal implants since it would eliminate overstimulation of the hyperactive retinal neurons in patients with degenerative eye disorders. A cortical prosthesis can also help patients who have a developed visual cortex and late-stage RP or AMD; their retinas are sometimes too damaged for retinal prostheses to work.
Researchers first attempted to develop cortical electrode arrays to recover vision in the 1960s (10). They implanted insulated steel wires in burr holes at the base of a patient’s skull. The patient, who had been blind for 18 years, could see flashes of light and distinguish between bright and low light. In their seminal publication in 1963, the researchers described it as “somewhat as the sun might appear to a sighted person through closed eyelids (11).”
Researchers have toyed with the idea of using cortical prostheses to recover vision in people with blindness, but the idea hasn’t been fully realized. Before Second Sight Medical Products discontinued the Argus II and announced a merger with Nano Precision Medical, they were testing a visual cortical prosthetic called the Orion Visual Cortical Prosthesis (Orion) in patients.
In May 2021, Second Sight Medical Products released data from a feasibility study conducted at the University of California, Los Angeles and Baylor College of Medicine where researchers followed six patients who received the device for two years. They reported that the patients saw improvements in vision, but the future of the Orion is unclear given the murky future of Second Sight Medical Products and their visual prosthetics.
Orion isn’t the only horse in the race for a cortical visual prosthesis. Philip Troyk, a biomedical engineer who develops neuroprosthetic devices at the Illinois Institute of Technology, leads a collaborative group of researchers from approximately 20 universities who are developing the Intracortical Visual Prosthesis (ICVP). The first ICVP device was implanted into a patient in February 2022 at Rush University Medical Center as part of a Phase I clinical trial.
It's taken more than 20 years to get to this point. Troyk started working with other groups funded by the NIH who were interested in developing a prosthetic like the ICVP in 2000. “We didn’t realize it was going to take 22 years to get to the point where we could actually test the feasibility,” he said.
“We had to develop technology that had not been conceived,” said Troyk. “In the past 20 years we have been working to refine the technology and define the parameters of a clinical trial in which we could actually test a large number of electrodes fully implanted [in the brain] with no transcutaneous connection across the skin, no connector on the head, nothing like that, and have the interface be stable and one that could be used chronically.”
Troyk’s team developed miniaturized modules they call “wireless floating micro electrode arrays.” The modules each have sixteen micro electrodes and are about the size of the button on top of a battery. Each microelectrode is covered with penetrating electrodes that allow it to be implanted into the cortex. The modules have a small, coil of wires inside that wirelessly communicates with a camera that Troyk said will likely be mounted on glasses or goggles.
“It’s kind of like a little miniature cell phone network in your head. We can call up each device and command it to put so much current from each electrode. With a multitude of these modules across the occipital lobe of the brain, we are striving to form an artificial vision neural interface,” said Troyk. “It’s very much like the Argus, except instead of having electrodes on the retina, the electrodes are inserted in the brain.”
The first patient in the trial had 25 modules implanted in February, making a final tally of 400 electrodes. Troyk is ready to test the patient’s visual skills after recovery from surgery, but he knows that there is a long road ahead before these devices become commonplace.
“There’s geometry to the retina that you can rely upon. When you go to the brain, you don’t have that luxury. When you insert an electrode into the brain, you don’t really know what the nature of the perception will be or where it will be in the person’s field of view. The first thing to do is map, for each of the electrodes, where and what they perceive when it’s stimulated,” said Troyk.
The plan is to stimulate the 400 electrodes one at a time to develop a map of the brain’s visual perception. Troyk and his colleagues previously implanted electrodes in mice, but this is the first opportunity scientists have to map how to communicate image information to the human brain.
“Unfortunately, there isn’t an instruction manual on how to communicate with the brain. This is something that really has to be discovered. And to a large extent, that’s the goal of the study: to determine that if we have such an interface, how can we use it?” said Troyk.
References
- Sahel, J. et al. Partial recovery of visual function in a blind patient after optogenetic therapy. Nat Med 27, 1223-1229 (2021).
- Cruz, L et al. Five-year safety and performance results from the Argus II retinal prosthesis system clinical trial. Ophthalmology 123, P2248-2254 (2016).
- Schaffrath, K. et al. One-year safety and performance assessment of the Argus II Retinal Prosthesis: A postapproval study. JAMA Ophthalmology 137, 896-902 (2019).
- Humayun, MS et al. Visual perception elicited by electrical stimulation of retina in blind humans. Arch Ophthalmology 114, 40-46 (1996).
- Jones, B.W. et al. Retinal remodeling triggered by photoreceptor degenerations. J Comp Neurol 464, 1-16 (2003).
- Farris, R.N. et al. Abnormalities in rod photoreceptors, amacrine cells, and horizontal cells in human retinas with retinitis pigmentosa. Am J of Ophthalm 129, P215-223 (2000).
- Jones, B.W. et al. Retinal Remodeling and Metabolic Alterations in Human AMD. Front Cell Neurosci 10 (2016).
- Palanker, D. et al. Photovoltaic restoration of central vision in atrophic age-related macular degeneration. Ophthalmology 127, 1097-1104 (2020).
- Humayun, M.S. et al. Interim results from the international trial of Second Sight’s visual prosthesis. Ophthalmology 119, P779-788 (2012).
- Lewis P.M. and Rosefeld, J.V. Electrical stimulation of the brain and the development of cortical visual prostheses: An historical perspective. Brain Res 1630, 208-224 (2016).
- Button, J. and Putnam, T. Visual responses to cortical stimulation in the blind. J Iowa State Med Soc 52, 17-21 (1962).
