Second sight.
Text: Angelika Jacobs
Currently there is no medical treatment that can restore vision. Researchers at Basel University plan to change that.
The fear of going blind is just as strong as fears of getting cancer or Alzheimer’s disease. It’s a fact that has been demonstrated by numerous surveys. In industrialized countries, age-related macular degeneration and inherited retinal diseases are among the most common causes of blindness. “Research on therapies aimed at restoring eyesight has made little progress for a long time now,” says Bence György. György, a researcher at the Institute of Molecular and Clinical Ophthalmology Basel (IOB), which is affiliated with the University of Basel, works with his team to translate findings from basic research into clinical practice.
While there have been many attempts by international research groups to restore vision to blind patients, most have failed. Today, researchers are placing their hopes on gene therapies. Teams all over the world are working to repair gene mutations in the retina or replace defective genes with the aim of stopping blindness in its tracks. Yet all these efforts will be in vain if the underlying genetic causes of blindness remain unclear, as is the case with age-related macular degeneration.
These gene therapies also have to be initiated at an early stage. In contrast to these therapies which aim to slow down progression, nobody can reverse advanced or total blindness – at least not yet. But György and his research group are working on a method to restore light sensitivity to blind retinas: They provide new light sensors to photoreceptor cells that have lost theirs.
First things first: The retina is composed of multiple layers. One layer consists of photoreceptor cells, specifically the cone cells that allow for high resolution, color vision, and the rod cells that facilitate low-resolution night vision. Then come two more layers: the bipolar cells and the ganglion cells. Neither respond to light, but they transmit the signals sent by the cone and rod cells. Finally, the ganglion cells transmit these stimuli to the brain via the optic nerve.
A first, partial success
A few years ago, the research team headed by Botond Roska, a professor at the University of Basel and co-director of the IOB, succeeded in inserting a light-sensitive protein into ganglion cells. In this way, a patient who had lost his sight to hereditary retinitis pigmentosa regained partial vision.
Yet the images he now perceives are anything but clear. “When we make the ganglion cells light-sensitive, we are circumventing much of the processing that takes place in the retina,” explains György. Hence the blurriness.
For that reason, György and his team decided to investigate whether the retinas of blind patients still contained photoreceptor cells that could be reactivated to sense light again. They focused on the cone cells, the main players in our day-to-day vision. The cone cells are densely packed in the fovea centralis, a pit that captures the middle of our field of vision. These cells allow us to do things like read, or recognize faces.
In the EyeConic study, the researchers studied the fovea centralis of around 400 fully blind eyes in 286 patients. They found that the fovea centralis still contained cone cells in nearly two-thirds of cases. And in one-third of cases, the number of cone cells was roughly normal.
“That came as a surprise, and it’s a key prerequisite for our idea to develop a broadly applicable therapy that works for many people – not just one small group of patients,” says György. Closer analyses produced a clearer picture: A protruding segment of the cone cells, the part containing the light-sensitive proteins, degenerates. For the most part, the cell body survives, but no longer responds to light.
New light sensors for blind cells.
“The next problem was to determine how to fit the cone cells with a new light sensor,” explains György. His team turned to optogenetics, a technique that revolutionized the neurosciences around 20 years ago. It involves using molecular biological methods to imbed light-sensitive proteins into nerve cells so that they can be activated using light.
The team developed and tested an optogenetic sensor using human retinas, which had been recovered from organ donors and are generally unsuitable for transplantation. For the past few years, it has been possible to preserve human retinas in the laboratory, but even here, the cone cells lose their light-sensitivity within hours of being recovered.
By placing a donor retina on a fine mesh of electrodes, it is possible to measure its dwindling activity. After the researchers used gene therapy to implant the genetic blueprint for the light sensor, the retina showed renewed activity in response to light, even several weeks after being recovered. Animal trials produced equally promising results.The type of vision this produces should be relatively similar to that of a healthy eye, albeit with somewhat lower resolution.
Moreover, the patient would perceive images in black and white. It is not yet possible to equip the different types of cone cells that receive blue, green and red light with sensors to detect different wavelengths of light. This remains on the list of potential developments to the therapy that could take place down the line if the approach proves successful in clinical practice.
To advance the therapy in the meantime, the researchers have founded RhyGaze (www.rhygaze.ch), a spin-out company based in Basel. György expects initial clinical trials on completely blind patients who still have cone cells in their retinas will begin in 2026. These studies will show whether the researchers’ hopes come true and the therapy allows blind people to regain much of their vision.
More articles in this issue of UNI NOVA (November 2024).