Experimental Eye Drops Help Blind Mice Regain Vision-Related Behavior

Photoreceptor degeneration underlies major causes of blindness such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), which together affect roughly 200 million people worldwide and cost the world more than US$400 billion a year in healthcare and lost productivity. A consortium led by the Institute for Bioengineering of Catalonia (IBEC) in Spain has developed light-activated small-molecule drugs that restored vision-related behavior in blind mice and zebrafish, a study in the Journal of the American Chemical Society (JACS) reports.

The compounds, called prosthe6, use photopharmacology, attaching a light-sensitive molecular switch to a drug so light can reversibly control its activity. They target ON-bipolar cells, retinal neurons that normally relay signals from photoreceptors, by acting on a protein called mGlu6. In AMD and RP, photoreceptors die but deeper retinal circuitry often stays intact though inactive, and prosthe6 is designed to substitute for some of that lost function.

In blinded zebrafish larvae, a model used to study visual acuity, the compounds restored saccadic eye movements known as the optokinetic reflex. In mouse models of AMD and RP, treated blind mice regained their instinctive, untrained preference for darker over brightly lit spaces, a behavior healthy mice show but blind mice lose. The effect occurred at illumination levels similar to indoor lighting or an overcast day. Two compounds, prosthe6-12 and prosthe6-15, worked best, whether injected into the eye or applied as eye drops.

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

The findings build on more than 10 years of research and involved teams led by Pedro de la Villa at the University of Alcalá (UAH), together with the University of Barcelona and the Institut de Química Avançada de Catalunya (IQAC-CSIC), among other Spanish research centers.