Key Takeaways

• Researchers developed photoswitchable prosthe6 compounds that restored vision-related behaviors in zebrafish and mouse models of retinal degeneration without requiring gene therapy or implanted retinal prostheses
• The compounds target ON bipolar cells through the mGlu6 pathway, functioning under ambient visible light and demonstrating activity following both intraocular injection and topical eye-drop administration in preclinical studies
• The technology remains in preclinical development, with ongoing safety, formulation, and translational studies aimed at advancing the compounds toward future clinical trials

Researchers led by the Institute for Bioengineering of Catalonia (IBEC) in Barcelona, Spain, have developed a new class of photoswitchable small-molecule compounds that restored vision-related behaviors in animal models of retinal degeneration, advancing a noninvasive approach to vision restoration that does not require gene therapy or implanted devices.

The findings, published in the Journal of the American Chemical Society, and detailed in an article on the IBEC website, describe a family of photopharmacological compounds known as prosthe6, which are designed to mimic the function of lost photoreceptors by reactivating preserved retinal circuitry. The compounds demonstrated preliminary safety profiles and restored visual function in zebrafish and mouse models of blindness caused by retinal degeneration.¹

Photoreceptor degeneration underlies conditions including age-related macular degeneration (AMD) and retinitis pigmentosa (RP), which together affect an estimated 200 million people worldwide. While the downstream retinal network often remains structurally intact, it no longer receives the light input necessary to transmit visual information to the brain. Existing vision restoration strategies—including gene therapy, retinal prostheses, and optogenetics—have shown promise but remain limited by mutation specificity, invasiveness, or the need for specialized equipment.

The IBEC-led consortium sought to restore visual signaling by targeting the retina at a point that more closely resembles natural vision.

"These molecules do not cure blindness, because they do not address the cause of photoreceptor degeneration," said Pau Gorostiza, PhD, ICREA research professor at IBEC and co-leader of the study. "But they are remarkably effective at restoring sight, and they do so using a very simple and potentially patient-friendly approach."

Photopharmacology uses light to reversibly control the activity of therapeutic compounds. To create prosthe6, investigators modified drug molecules with light-sensitive molecular switches that change conformation in response to visible light, enabling light-dependent activation of retinal signaling pathways. Rather than bypassing retinal processing, the compounds target ON bipolar cells, which normally receive input directly from photoreceptors.

"Our goal was to restore vision using a molecular mechanism that is as close as possible to how the healthy retina works," said co-first author Rosalba Sortino, PhD, currently a postdoctoral researcher at IBEC. "Instead of bypassing retinal processing, we aimed to reactivate it right at the same level of the retinal circuit as the lost photoreceptor cells."

In blinded zebrafish larvae, prosthe6 restored optokinetic responses, a commonly used measure of visual function. In mouse models of AMD and RP, treatment restored innate light-avoidance behavior. Normally sighted mice preferentially remain in dark environments, whereas blind mice lose this behavior because they cannot detect light. Following treatment, blind mice again demonstrated a spontaneous preference for dark environments under lighting conditions comparable to typical indoor illumination or an overcast day. According to the investigators, the recovery occurred without behavioral training, suggesting restoration of functional light perception sufficient to guide natural behaviors.

The researchers reported that prosthe6 activates the metabotropic glutamate receptor 6 (mGlu6) pathway in ON bipolar cells, effectively replacing the signaling normally provided by photoreceptors. Upon exposure to light, the molecules undergo a structural change that initiates retinal signaling in a manner intended to resemble physiological visual processing.

Unlike some optogenetic approaches, the compounds were designed to function under ambient visible light and do not require high-intensity illumination or external light-amplifying devices. The molecules are also water soluble, potentially enabling multiple routes of administration.

The work builds on more than a decade of research and involved investigators from the University of Alcalá, the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), the University of Barcelona, the Ramón y Cajal Institute for Health Research (IRYCIS), the Autonomous University of Barcelona, and the Fundació Eduard Soler.

According to the research team, the prosthe6 platform is protected by patent, and ongoing efforts are focused on optimizing formulation, evaluating safety, and extending the duration of visual restoration. The investigators are also collaborating with Eyelumina, a spin-off company in formation, to support translational development and future clinical studies.

Reference

1. Sortino R, González-Díez A, Milla-Navarro S, et al. Restoration of saccadic eye movements and visually guided behavior in ambient white light with photoswitchable small molecules. J Am Chem Soc. Published online July 15, 2026. doi:10.1021/jacs.5c18611.