Light encountering the eye is sensed by cells expressing photoreceptors, which transform light signals into electric signals sensed by the retinal ganglion cells that transmit these signals to the brain. In degenerative eye diseases such as retinitis pigmentosa and macular degeneration, these light-sensitive cells gradually die off, resulting in progressive blindness.
To treat these diseases, some researchers are designing retinal prostheses that elucidate the “code” of electrical pulses recognized by retinal ganglion cells. Others are examining methods to make the ganglion cells themselves sensitive to light. And now a third strategy from researchers at Cornell University, published today (August 13) in Proceedings of the National Academy of Sciences, draws on both efforts by creating a system wherein the retinal ganglion cell code is transformed into light pulses that signal to transgenic neurons expressing with a light-sensitive receptor.
“We do need alternatives [to current devices],” said James Weiland at Doheny Vision Research Center at the University of Southern California, who did not participate in the research. Retinal implants have been used in patients, he said, but “results have been limited.”
For example, the retinal prosthetic company Second Sight, which collaborates with Weiland, uses implantable electrodes that receive signals from a camera worn on sunglasses. Digital images from the camera are transformed into electrical pulses based on pixel brightness, which are wirelessly transmitted to an electrode array in the patient’s eye. Pulses from the electrodes stimulate retinal neurons, including retinal ganglion cells. Results from a recent clinical trial demonstrate that patients with retinitis pigmentosa can regain some visual function, such as detecting motion and locating objects, and that these patients can achieve 20/1262 sight. But Sheila Nirenberg at Cornell argues that this is not enough, given that 20/200 is legally blind.
One reason for this limited success may be that Second Sight’s implanted electrodes do not fire in the same patterns as the retinal ganglion cells of people with normal vision. Retinal ganglion cells stimulated by light-sensitive cells fire specific patterns in response to specific images, which allows us to distinguish different objects, such as trees from faces. To restore significant sight, Nirenberg, like many other researchers, believes that a medical device must stimulate the retinal ganglion cells in blind patients’ eyes to send the same signals as in sighted eyes. In other words, retinal prostheses must find a way to “encode” an image entering the eye, such as a face, into a signal pattern that will prompt the retinal ganglion cells in a blind retina to fire the same pattern stimulated by the face in a sighted retina.
To achieve this, Nirenberg and her colleagues designed a system combining an “encoder” and projector. The encoder transformed images, like a child’s face, into the correct pattern of light pulses, which was then projected to retinal ganglion cells that had been transfected with the light-sensitive receptor channelrhodopsin 2 (ChR2). Using isolated mouse retinas, the researchers demonstrated that images transformed into light pulses could stimulate the ChR2-expressing ganglia to fire in a pattern similar to sighted retinas. If the ChR2-expressing ganglia were only exposed to the image, however, they fired in a different pattern, suggesting that the encoder would be necessary to provide the brain with a true visualization of the face.
To show that the light pulses could improve sight in blind mice, Nirenberg looked at eye tracking. She immobilized mice to allow the encoder to aim its light into their eyes. Blind ChR2-expressing mice cannot track external stimuli (in this case a sine wave displayed on a screen), but their eyes changed course when the stimulus was transformed into light pulses. Nirenberg envisions a prosthetic device mounted on eyeglasses, wherein the encoder transforms images captured by camera into light pulses that are projected from the camera into the eye.
But other retinal prosthesis researchers are skeptical of Nirenberg’s approach. Any potential prosthetic based on this strategy faces similar technical challenges as other implants designed to send encoded signals to retinal ganglion cells, explained E.J. Chichilnisky, who studies retinal encoding and prosthesis design at the Salk Institute, but was not involved in the research. There about 20 different ganglion cell types that transmit different signals to different targets in the brain, each of which will need a different encoder. Making sure that each is targeted by the right code of light pulses will be difficult, given that the different cell types are intermingled and hard to identify, and the eye is constantly moving, he said.
“The brain will be confused,” agreed Daniel Palanker, who also works to create vision-restoring retinal implants at Stanford University, but did not participate in the research. “It will be expecting many different codes, but the implant will deliver one code from many different cells.”
This drawback also plagues other strategies, like Second Sight’s, Weiland explained, though he doesn’t think this is a deal-breaking stumbling block. The projector “is stimulating the ganglion cells indiscriminately… but in [other systems] people can still see light and do simple tasks,” he said. “You don’t need to perfectly recreate signals of the retina” to improve patients’ sight.
Additionally, there are many challenges involved in using gene therapy to express a photosensitive receptor in human patients' eyes, a strategy which has yet to make it past the animal testing phase. “Genetic transfection in clinical trials is usually limited to life and death,” noted Jessica Winter, who engineers biocompatible coatings for neural prostheses at Ohio State University, but was not involved in the research. “How blind does a patient have to be to risk this?”
Even if such genetic hurdles were overcome, ChR2 may not be the ideal photoreceptor for ganglion cells. Photoreceptors in the eye can amplify the energy of one photon 100,000 volts, allowing sight in natural light conditions—which ChR2 cannot yet do. As a result, the high light levels required to stimulate a transfected receptor may be intolerable for patients who retain any light sensitivity, Chichilnisky explained. “The transducer [ChR2] needs to become more sensitive,” Weiland agreed.
S. Nirenberg, C. Pandarinath, “Retinal implant with capacity to restore normal vision,” Proceedings of the National Academy of Sciencse, doi: 10.1073/pnas.1207035109, 2012.