Photoreceptor degeneration is behind several important causes of blindness, including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Together, these disorders affect approximately 200 million people worldwide and are among the leading causes of visual impairment and blindness. Beyond the profound effects on independence and quality of life, vision loss also creates a global economic burden estimated at more than $400 billion annually through healthcare expenses and lost productivity.
In these diseases, the retina’s photoreceptor cells, which detect incoming light, gradually deteriorate and die. However, much of the retina’s deeper neural circuitry may remain intact and able to function. The problem is that, without photoreceptors, these surviving cells no longer receive the light signals necessary to send visual information to the brain.
That remaining retinal circuitry has become an important target for scientists trying to restore light sensitivity. Existing approaches include gene therapy, which is suitable for only a small fraction of patients with particular mutations, and electronic retinal prostheses, which can be invasive, expensive and require significant training. Optogenetics and light-responsive drugs have also entered clinical trials. Light-responsive drugs have produced encouraging safety results, but restoring high-quality vision under normal lighting levels remains difficult.
Light-activated drugs offer a new approach
A research consortium led by the Institute of Bioengineering of Catalonia (IBEC) has developed a new class of photoswitchable small molecule drugs designed to restore important visual functions in animal models of blindness. The findings were published in the Journal of the American Chemical Society (JACS).
The compounds are designed to take over some of the work that photoreceptors normally do. They can be administered by injection into the eye, like other ophthalmic drugs, or even applied as eye drops. Neither method requires genetic modification or an implanted device. The compounds have also shown promising safety profiles, making them potential candidates for future therapies aimed at restoring vision.
“These molecules do not cure blindness, because they do not address the cause of photoreceptor degeneration, but they are remarkably effective in restoring sight, and they do so through 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 the CIBER-BBN and co-leader of the study.
“Our goal was to restore vision using a molecular mechanism as similar as possible to the functioning of the healthy retina,” says Rosalba Sortino, former doctoral student at the University of Barcelona, currently a postdoctoral researcher in Gorostiza’s group at the IBEC and co-first author of the study. “Rather than bypass retinal processing, our goal was to reactivate it at just the same level of retinal circuitry as the lost photoreceptor cells.”
The results are based on more than 10 years of research. The team led by Pedro de la Villa at the University of Alcalá (UAH) participates in the project, along with researchers from the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), the University of Barcelona (UB), the Ramón y Cajal Institute for Health Research (IRYCIS), the Autonomous University of Barcelona (UAB) and the Eduard Soler Foundation.
Restoration of visual function in blind animals
The technique is based on photopharmacology, an approach that allows the activity of a drug to be reversibly controlled using light. Researchers alter the chemical structure of a drug by incorporating a light-sensitive molecular switch. When exposed to light, the switch changes the activity of the drug.
Using this strategy, the team created a family of compounds known as prosthe6. These molecules target ON bipolar neurons and restored saccadic eye movements (optokinetic reflex) in blind zebrafish larvae, a model commonly used to investigate visual acuity.
The researchers also found that the treatment could restore innate light avoidance behavior in mouse models of age-related macular degeneration and retinitis pigmentosa.
Healthy mice instinctively prefer darker environments and avoid brightly lit spaces. This behavior depends entirely on a functioning visual system. Blind mice lose that preference because they cannot detect the difference between light and dark.
However, after receiving prosthe6, blind mice spontaneously preferred dark areas again. This behavior indicated that they were able to detect light and use visual information to guide their actions. No training was necessary.
The effect also occurred at lighting levels similar to those found indoors or outdoors on a cloudy day. This suggests that the treatment restored functional light perception strongly enough to produce natural, visually guided behavior.
Two compounds in particular, prosthe6-12 and prosthe6-15, produced especially promising results. Restored visual behaviors appeared after injection into the eye and also after topical administration in the form of eye drops.
Replacing the function of lost photoreceptors
Prosthe6 works by targeting bipolar cells, the neurons in the retina that normally receive information from photoreceptors, the cells responsible for detecting light.
“In healthy vision, ON bipolar cells play a key role in transmitting information about the presence of light to the rest of the visual circuit. In degenerative eye diseases, although photoreceptors are lost, much of this underlying circuit remains intact but inactive. This creates an important therapeutic opportunity,” explains de la Villa, co-leader of the study.
The compounds target a protein (mGlu6) within this surviving retinal circuit. By doing so, prosthe6 can effectively replace some of the functions normally provided by missing photoreceptors.
When light hits the eye, the molecules change shape. That change triggers signals within the retina in a way that resembles normal visual processing. The researchers describe the compounds as “molecular prostheses” because they allow the retina to respond to light again without hardware implants or genetic modifications.
Another important feature is its ability to operate under normal lighting. Unlike some optogenetic approaches, they do not require devices that amplify or deliver specialized light. The molecules are small and water-soluble, and respond to common visible or white light, including normal indoor lighting and daylight, without the need for unusually intense or specialized light sources.
Moving towards possible human treatments
The findings come shortly after the publication of the first clinical trial of a photopharmacological drug for vision restoration (which targets an unrelated protein). That milestone suggests that photopharmacology is beginning to move from experimental research to potential clinical use.
The prosthesis technology6 is patent protected and researchers are now studying its safety and formulation with the goal of extending the duration of restored visual function.
The team is also working with Eyelumina, a spin-out company in the making, to secure investments to 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, reversible and with a mechanism that is independent of the specific retinal disorder or genetic mutation to reach the majority of patients.”
If the approach ultimately proves successful in people, it could provide a widely accessible and affordable alternative to current vision restoration technologies. It could be particularly important for people with advanced retinal degeneration who currently have no effective treatment options.
The project received advance funding from the Fundaluce patient foundation (2016), CaixaHealth (Drug4sight, 100010434), the Generalitat of Catalonia (Innovadors, Producte and Peris programs) and CIBER-BBN (valorization program).
The work was also part of Rosalba Sortino’s doctoral thesis. The University of Barcelona awarded him the Extraordinary Doctorate Prize for the 2023-24 academic year for the thesis he presented at the Faculty of Pharmacy and Food Sciences.