A consortium led by the Institute for Bioengineering of Catalonia (IBEC) developed this approach based on photopharmacology, a technique to reversibly control drug activity with light. The newly developed compounds, called prosthe6, mimic the function of photoreceptor cells, which degenerate in blinding diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). These photoswitchable molecules show preliminary safety profiles and represent potential drug candidates for restoring vision in patients with degenerative retinal diseases, without the need for genetic manipulation or implanted devices.

In many blinding diseases, photoreceptor cells — the retina’s light detectors — progressively degenerate and die. Although the downstream retinal neuronal circuitry remains largely intact and functionally viable, it no longer receives the light signals needed to drive visual processing towards the brain. This opportunity has fuelled intense research efforts to develop treatments capable of restoring light sensitivity to the eye. Current strategies include gene therapy — effective only for a very small subset of patients with specific mutations — and electronic retinal prostheses, which are invasive, expensive, and require extensive training for effective use. More recently, optogenetics and light-responsive drugs have entered clinical testing, the latter with encouraging safety results, but achieving high-quality vision at ambient illumination levels remains a major challenge.

The study, published in the Journal of the American Chemical Society (JACS), presents a new class of photoswitchable small-molecule drugs capable of restoring key visual functions in animal models of blindness. Compounds can take over the functional role of photoreceptors by injecting them in the eye as done with other ophthalmic drugs, or even by administering eye drops. In either case, they do not require genetic manipulation or implanted devices. Moreover, the compounds show promising safety profiles that position them as potential drug candidates for future vision restoration therapies.

“These molecules do not cure blindness, because they do not address the cause of photoreceptor degeneration. But they are remarkably effective at restoring sight, and they do so using a very simple and potentially patient-friendly approach”, explains Pau Gorostiza, ICREA Research Professor at IBEC, leader of the Nanoprobes and Nanoswitches group, member of CIBER-BBN and co-leader of the study.

“Our goal was to restore vision using a molecular mechanism that is as close as possible to how the healthy retina works,” says Rosalba Sortino, former PhD student at the University de Barcelona, currently post-doctoral researcher at Gorostiza’s group at IBEC and co-first author of the study. “Instead of bypassing retinal processing, we aimed to reactivate it right at the same level of the retinal circuit than the lost photoreceptor cells.”

The work builds on more than a decade of research and was carried out in collaboration with the team led by Pedro de la Villa at the University of Alcalá (UAH), as well as researchers from the Institut de Química Avançada de Catalunya (IQAC-CSIC), the University of Barcelona (UB), the Institute Ramón y Cajal of Health Research (IRYCIS), the Autonomous University of Barcelona (UAB), and the Fundació Eduard Soler.

Restoring visual function in animal models

The approach is based on photopharmacology, a technique in which drug activity can be reversibly controlled with light. This innovative technique involves modifying a drug’s chemical structure by adding a light-activated molecular switch that allows controlling the pharmacological action with light. With this aim, the researchers developed a family of compounds called prosthe6 that target ON-bipolar neurons and successfully restored saccadic eye movements (optokinetic reflex) in blinded zebrafish larvae, a widely used model for studying visual acuity. Even more strikingly, the researchers demonstrated recovery of innate light-avoidance behaviour in mouse models of age-related macular degeneration and retinitis pigmentosa.

Healthy mice naturally prefer to remain in dark environments and instinctively avoid brightly lit areas, a behaviour that relies entirely on a functional visual system. Blind mice, by contrast, lose this preference and move indistinctly between light and dark spaces, as they are unable to perceive light. After treatment with prosthe6, the blind mice once again showed a clear and spontaneous preference for dark areas, indicating that they could perceive light and use this information to guide their behaviour. This recovery occurred without any training and under light levels comparable to those found indoors or on an overcast day, demonstrating that the treatment restores functional light perception capable of driving natural, visually guided behaviour.

Two lead compounds, prosthe6-12 and prosthe6-15, showed particularly promising results. The restored behaviours were observed not only after intraocular injection, but also after topical administration as eye drops.

Targeting the retina at the right place

The prosthe6 compounds work by acting on a specific type of retinal cells called ON bipolar cells, which normally receive signals from the photoreceptors, the eye’s light-sensing cells.

“In healthy vision, ON bipolar cells play a key role in passing on information about the presence of light to the rest of the visual circuit. In degenerative eye diseases, although the photoreceptors are lost, much of this underlying circuitry remains intact but inactive. This creates a major therapeutic opportunity,” explains de la Villa, co-leader of the study.

By targeting a protein (mGlu6) in this preserved part of the retina, prosthe6 compounds can take over the role of the missing photoreceptors. When light enters the eye, the molecules respond by changing their shape, triggering signals inside the retina in a way that closely resembles natural vision. In this way, the drugs effectively act as “molecular prostheses”, helping the eye process light again without the need for implants or genetic modifications.

Importantly, these compounds are designed to work under normal lighting conditions and do not require light-enhancing devices as optogenetics. They are small, water-soluble molecules that respond to ordinary visible or white light, such as indoor lighting or daylight, without requiring intense or specialised light sources.

» Article of reference: Rosalba Sortino, Aleix González-Díez, Santiago Milla-Navarro, Joaquín Martínez-Tambella, Víctor Paleo-García, Eric Calatayud, Paula de Saralegui, Ekin Opar, Àlvar Claparols, Josecarlo A. Quintanilla, Xavier Martínez-Soler, Fabio Riefolo, Carlo Matera, Jordi Hernando, Alexandre M. J. Gomila, Gerard Pérez-Batlle, Carles Pereira, Núria Cambrer, Carme Serra, Xavier Gómez-Santacana, Amadeu Llebaria, Xavier Rovira, Pedro de la Villa, Pau Gorostiza. Restoration of saccadic eye movements and visually guided behavior in ambient white light with photoswitchable small molecules. Journal of the American Chemical Society (2026). DOI: https://www.doi.org/10.1021/jacs.5c18611

» Link to the news: IBEC website [+]