Optogenetics, goggles increase visual perception in case of inherited retinal dystrophy
Optogenetic stimulation of the retina with a treatment combining injection of photoactivatable channelrhodopsin protein and light-stimulating goggles showed the ability to partially restore vision in late-stage retinitis pigmentosa.
José-Alain Sahel, MD, and co-authors published in Nature Medicine the case of one patient with retinitis pigmentosa (RP) and only light perception who was able, after the treatment, to perceive, locate and reach objects in space. The patient was one of the participants in the PIONEER study, evaluating the safety and efficacy of Bionic Sight’s GS030-DP, a sensitive optogenetic protein injected intravitreally and activated via light-stimulating goggles (GS030-MD).
Marco Zarbin, MD, PhD, welcomed the success of this mutation agnostic therapy as a further step forward after retinal prostheses, which involve an extensive surgical procedure and may have more limited potential for restoring vision.
“The Argus II (Second Sight) has 60 electrodes, which are 60 points of stimulation. Optogenetics can transform, in principle, millions of cells to become light sensitive. In addition, this procedure from a surgical perspective is far simpler. You just inject the virus into the eye. We do injections into the eye every single day as retinal surgeons,” he said.
Ganglion cells are made light sensitive
Optogenetics is a field of science in which cells that are normally not light sensitive are made light sensitive by compelling them to express light-sensitive proteins. These proteins can be light-activated ion channels that gate the flow of ions across the cell membrane, inducing a change in the membrane potential, which leads to signal propagation, Zarbin said.
“Normally the cells that are sensitive to light in our eye are the photoreceptor cells (although there is a small subset of light-sensitive ganglion cells that are involved in the circadian rhythm and the pupillary light response), but in retinitis pigmentosa, the photoreceptor cells die. Bionic Sight’s approach is to bypass the photoreceptors and go directly to the ganglion cells, turning them into cells that are light sensitive,” he said.
The pathway to this approach, however, was not so straightforward, and several questions arose about its feasibility.
In a healthy retina, the visual information undergoes extensive processing. The photoreceptors capture the light and convert it into a chemical signal that is processed through the various layers of the retina and eventually delivered to the brain via the ganglion cells.
“So, usually the ganglion cells are the output cells, the last messenger in the chain of communication between the eye and the brain. In this case, they are not only the last but also the first messenger of communication, and a lot of that extensive processing is lost. In addition, ganglion cells are of many types and are divided into on-ganglion cells and off-ganglion cells. This approach may be making all the ganglion cells one type: on-ganglion cells. So, questions arose on whether there would be any useful visual information that could be developed through this type of approach,” Zarbin said.
The experiment dispelled all doubts, providing evidence that was conclusive.
“This person could only see the light before the experiment. Now he can recognize objects on a table and stripes on the street. This is not the same as being able to read The New York Times, but it is a dramatic improvement for someone with advanced-stage blindness,” he said.
More on the experiment
The patient was a 58-year-old man diagnosed with RP 40 years ago. The treatment consisted of a single injection of an adeno-associated viral vector encoding ChrimsonR, a light-sensing protein with a peak sensitivity of 590 nm, the wavelength of amber color light.
“This is a safer wavelength as compared with other types of light-sensing proteins currently in clinical trials that tend to absorb closer to 495 nm,” Zarbin said.
Because ChrimsonR does not have the same light sensitivity as the natural light sensitive proteins of the eye (ie, rhodopsin, cone opsin), which are exquisitely sensitive to light, specifically designed goggles were critical for achieving visual improvement. The goggles, which amplify the external stimulus, eliminate the need for extremely bright ambient light to activate the optogenetic protein. When tested without goggles, the patient was unable to see with one or both eyes the objects placed on a white table, while the addition of goggles enabled him to perceive, locate and touch single and multiple objects of various sizes and at different contrasts. Further evidence of vision recovery was provided by electroencephalography, which showed changes in the occipital cortex signals related to the presence or absence of the visual objects.
“This shows how close we can be to success, yet draw the wrong conclusions from an experiment. If Dr. Sahel and his team had performed the experiment with just injecting the vector, they would conclude that it does not work, and that would be the wrong conclusion. But because they were farsighted enough to provide the goggles, we now know it works,” Zarbin said.
Because preclinical experiments had shown that the peak of gene expression was achieved between 3 months and 6 months from the time of injection, the patient was scheduled for his first session of visual training with the light-stimulating goggles at 4 months and did not start reporting signs of visual improvement until 7 months later.
“This result may mean that the visual system, including the eye and the brain, needs some time to be able to interpret the visual signals that it is receiving. There may be an adaptive response here that contributes to the effectiveness of the therapy,” Zarbin said.
“That’s what I think the good news is: a mutation-agnostic therapy recovering useful vision for people severely disabled with vision loss, but requiring the goggles, requiring the time for the treatment to work, requiring a training period and an adaptation period,” Zarbin said.
Besides the groundbreaking work of Sahel and colleagues, there are several other promising optogenetic studies in the pipeline. At the University of California, Berkeley, John Flannery, PhD, and colleagues have been working on transfecting ganglion cells with a natural light-sensitive molecule of the photoreceptors, the green cone opsin.
“This molecule is much more light sensitive than the light-sensitive ion channels, and maybe the patient would not need goggles with this molecule,” Zarbin said.
Another line of research, pursued by Nanoscope Therapeutics, aims at making bipolar cells light sensitive by delivering multi-characteristic opsins to the retina through a single intravitreal injection. This polychromatic opsin is activated in ambient light and requires no goggles. Preliminary results showed a visual acuity improvement of 15 letters or more and improvement in latency in a visually guided Y mobility test.
“It might be an even more promising approach because they not only use a molecule that is more light sensitive, but they are also targeting bipolar cells, which should allow more visual image processing within the retina. We are looking forward to additional information regarding the results of this study,” Zarbin said.
A further step forward in optogenetics will be the development of non-viral vectors. Viruses are naturally engineered to deliver cargos to cells and transform the behavior of millions of cells, but inflammation is a problem that is well recognized by scientists, with a potentially significant clinical impact.
“A promising alternative way to deliver proteins to cells is nanoparticles,” Zarbin said. “They could potentially deliver even larger cargos and have an even greater specificity for the target cells, but as promising as this approach is, it really has not moved forward in the way I was hoping it would. I suspect that, eventually, non-viral vectors will be the way we deliver DNA for the production of proteins in cells of the eye. But for now, the viral vectors are winning the race.”
- Sahel JA, et al. Nat Med. 2021;doi:10.1038/s41591-021-01351-4.