Retinitis pigmentosa is an inherited degenerative condition that destroys photoreceptors in the retina and can eventually lead to irreversible blindness. In a clinical trial first, an international research team has demonstrated that optogenetic therapy is safe to use and shows potential for restoring visual function in patients with late stages of this disorder.
In a first-in-human study in 2021, the collaboration – led by José-Alain Sahel from the University of Pittsburgh School of Medicine and Botond Roska from the Institute of Molecular and Clinical Ophthalmology Basel (IOB) – demonstrated that optogenetic therapy led to partial recovery of visual function in a blind patient with retinitis pigmentosa. This latest work, reported in the New England Journal of Medicine, expands the cohort to 10 participants.
Optogenetics is a method that uses light to characterize and manipulate the activity of neurons in the brain – and which earlier this week won its inventors the 2026 Nobel Prize in Physiology or Medicine. The optogenetic therapy developed by Sahel, Roska and collaborators combines gene therapy that makes surviving ganglion cells (neurons in the retina) sensitive to light with special goggles that stimulate the altered cells.
“Although patients with retinitis pigmentosa lose their rod and cone cells, which normally detect light, many other cells within the retina can remain present for years after vision loss,” explains Sahel, director of the UPMC Vision Institute and first author on this study. “Optogenetics enables us to introduce a light-sensitive protein into these surviving cells, allowing them to respond to light and transmit visual information to the brain. The therapy bypasses the damaged photoreceptors and takes advantage of retinal circuits that remain intact.”
Sahel notes that retinitis pigmentosa can be caused by mutations in any one of hundreds of different genes, making optogenetic therapy a particularly suitable approach as it can potentially help regardless of the underlying mutation.
Safe to use
In the study, 10 participants with blindness due to advanced retinitis pigmentosa were injected in their worse-seeing eye with a gene that produces ChrimsonR – a light-sensitive protein with a peak response at around 590 nm (amber). The team divided the subjects into three dose-escalation groups, receiving 5.0 x 1010, 1.5 x 1011 or 5.0 x 1011 vector genomes per eye.
The primary aim was to evaluate the safety of the optogenetic therapy. The researchers observed 33 mild and moderate adverse ocular events in nine of the participants, such as temporary inflammation and increases in eye pressure, plus one severe event, which resolved within minutes after treatment. They concluded that, within the limits of the study, the treatment was safe.
Using the light-stimulating goggles, they then assessed the visual performance of treated eyes, before and after injection. The goggles contain a camera that detects changes in light intensities pixel-by-pixel and converts this visual data into pulses of amber light. This light is projected onto the eye to activate ChrimsonR in the modified retinal ganglion cells. Vision tests revealed that the treatment increased light sensitivity in seven of the 10 participants, by a factor of 2.0 to 62.3, with six patients showing a clinically meaningful improvement.
The patients also performed a series of tasks to detect, localize and touch a notebook and a staple-box. In the notebook task, five of eight participants had higher accuracy when wearing the goggles than when not wearing them, while four showed improved accuracy in the staple-box task. In a task determining the orientation of a single bar, accuracy was higher with the goggles in five of eight participants.
To provide an objective measurement of brain activity in response to light, the researchers obtained electroencephalographic (EEG) recordings in five patients performing two visual tests: detection of a tumbler placed in front of them (with the eyes open or closed); and passive viewing of periodic visual stimuli.
In the tumbler test, EEG decoding accuracy was higher with goggles than without when the eyes were open, but not when they were closed – implying a genuine improvement in visual processing rather than an artefact. The second test also showed increased decoding accuracy, which correlated with mean improvements in the notebook and staple-box tasks.
A bright future
The changes in visual performance were consistent across multiple tasks and testing sessions, with responses observed in all three dose groups. Participants who spent longer being trained to use the goggles performed better in the visual behavioural tests. The researchers point out, however, that functional changes were modest: improving object detection and discrimination capabilities but not restoring normal sight. The small sample size also limited their ability to characterize treatment response.
Several projects are currently underway to further enhance the technology. This includes digital holographic goggles with an eye tracker being developed by the team of Valentina Emiliani at the Institut de la Vision in Paris. The system will project 20 µm-wide images that stimulate individual cells in the retina.
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“With the eye tracker, we can make sure we are projecting exactly onto the area of the retina that we want. We’ve already developed a prototype, and it is moving forward,” says Sahel.
Elsewhere, University of Pittsburgh scientists are working with Roska’s group to develop cell-specific gene therapy vectors. “There are different types of cells: some respond to the onset of light, some to the offset of light, some to movement and direction,” Sahel explains. “We are trying to selectively stimulate the ‘on’ and the ‘off’, and discriminate the signal we are sending.”
“We are optimistic about advancing this approach toward future clinical trials,” he tells Physics World.
