Blinding diseases caused by the degeneration of photoreceptors, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), affect 200 million people worldwide and represent the leading causes of visual impairment and blindness. Beyond the personal impact on quality of life and independence, vision loss places a global economic burden estimated at over US$400 billion per year in healthcare costs and lost productivity.
In many of these conditions, 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.
Now, a consortium led by the Institute for Bioengineering of Catalonia (IBEC) has made a major step forward in the quest to restore vision in humans. Published in the Journal of the American Chemical Society (JACS), the research 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.
From fundamental chemistry to translational science
The timing of the study is also significant: it follows shortly after the publication of the first-ever clinical trial of a photopharmacological drug for vision restoration (which targets an unrelated protein), highlighting that this emerging therapeutic strategy is in its way to reach patients.
The prosthe6 technology is protected by patent and the researchers are now evaluating its safety and formulation to extend the duration of visual rehabilitation. The team is also working with Eyelumina, a spin-off company in formation to secure investments that support translational development and future clinical trials.
"Turning this into a therapy is a long and laborious process," says Gorostiza. "But the results show that there is a realistic possibility of restoring high-quality vision with drugs, non-invasively, reversibly and with a mechanism that is independent of the specific retinal disorder or genetic mutation to reach a majority of patients."
If successful in humans, the drug-based approach would offer a widely accessible and affordable alternative to existing vision restoration technologies, especially relevant for patients with advanced retinal degeneration for whom no effective treatments currently exist.
This research received seed funding from the patients' foundation Fundaluce (2016), CaixaHealth (Drug4sight, 100010434), the Government of Catalonia (Innovadors, Producte, and Peris programmes), and CIBER-BBN (valorization programme).
This research is also part of Rosalba Sortino's doctoral thesis. She was awarded the Extraordinary Doctoral Prize for the 2023–24 academic year by the University of Barcelona for her thesis, which she presented at the Faculty of Pharmacy and Food Sciences.
About IBEC
The Institute for Bioengineering of Catalonia (IBEC) is a CERCA center, three times recognized as a Severo Ochoa Center of Excellence, and holds the TECNIO label as a technology developer and business facilitator. IBEC is a member of the Barcelona Institute of Science and Technology (BIST) and conducts multidisciplinary research at the forefront of engineering and life sciences to generate knowledge. The institute integrates fields such as nanomedicine, biophysics, biotechnology, tissue engineering, and applications of information technologies in the health sector. IBEC, established in 2005, is a collaborative effort of the Generalitat de Catalunya, the University of Barcelona (UB), and the Polytechnic University of Catalonia (UPC).
