Eye drops restored light-responsive behavior in blind mice through the surviving retina
Eye drops restored light-responsive behavior in blind mice through the surviving retina
On July 15, the Journal of the American Chemical Society published a study of prosthe6 photoswitchable molecules. In a model of geographic atrophy, two compounds applied to the eye surface restored the mice's preference for a dark compartment under ordinary white light. One of the compounds produced the same effect in a genetic model of retinitis pigmentosa.
The retina does more than detect light. Photoreceptors transmit signals to bipolar cells, while subsequent neuronal layers extract contrast, motion, and direction. Photoreceptors die in geographic atrophy, an advanced form of dry age-related macular degeneration, and in retinitis pigmentosa. Part of the retina's internal circuitry survives, but it no longer receives an input signal.
The authors targeted prosthe6 to the mGlu6 receptor in bipolar cells, the first stage after the photoreceptors. In a healthy eye, darkness maintains this receptor's activity, while light reduces it. Prosthe6 reproduces this pattern chemically. In darkness, the molecule activates mGlu6. White light changes the molecule's shape, causing it to stop activating mGlu6. The difference between light and darkness can therefore once again become a signal for the eye's remaining neural network.
The signal passes through later retinal layers, where visual information is normally processed. Earlier photoswitches often acted on ganglion cells, which are already at the retina's output. The authors confirmed that mGlu6 was involved: continuous activation of this receptor weakened the restored response to light.
The researchers tested a specific behavior in mice. Each animal could move freely between dark and illuminated compartments. Healthy mice prefer darkness, but this preference disappeared after retinal damage. It returned 2,5 hours after topical administration of prosthe6-12 or prosthe6-15. The eye-drop groups included 9–10 mice. In zebrafish larvae, prosthe6 also restored the eye movements used to track moving light and dark stripes.
The experiment measured whether a mouse could distinguish light from darkness and use that information to choose a direction. Reading, face recognition, and visual acuity require separate tests. The retina reorganizes after photoreceptors die: bipolar-cell processes retract, and their connections change. The authors observed an effect in a retinitis pigmentosa model in which the retina had already undergone this reorganization, but the human retina still needs to be tested separately.
Drug-based photoswitches have already reached human testing. Another compound, KIO-301, was injected into the vitreous of 12 eyes in six participants with severe retinitis pigmentosa in a phase 1 study. It acts on ganglion cells, which are located later in the retinal pathway. Prosthe6 offers a different approach: activating an earlier surviving part of the retina and delivering the molecule without an intraocular injection.
In rabbit eyes, prosthe6-12 remained detectable in the retina for up to six hours after administration as eye drops. Its retinal concentration may be lower in the larger human eye. The compound will require a suitable formulation, a longer duration of action, and safety testing for repeated doses. For now, prosthe6 provides a chemical replacement for the lost light input in animal models. It does not restore dead photoreceptors.