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Chemical Approaches to Restoring Vision

Final Report Summary - CARV (Chemical Approaches to Restoring Vision)

Light is a phenomenon that holds a special fascination for humans. It is unmatched in its ability to confer information with temporal and spatial precision and has been used to map objects on the scale of nanometers to light-years. The resulting information, gathered through super-resolution microscopes or space-based telescopes, is ultimately funneled through the human visual system, where the absorption of a photon triggers the isomerization of a molecular photoswitch, viz. retinal, in a photoreceptor cell.

This system, which is a miracle in terms of sensitivity and adaptation, can be severely damaged and becomes non-functional when the natural photoreceptor cells are gone. In many forms of blindness, such as retinitis pigmentosa of late-stage macular degeneration, this is the case. In this project, termed CARV, we have explored the use of synthetic photoswitches, in particular so-called azobenzenes, for the restoration if vision. Our photoswitchable molecules can bind covalently or non-covalently to a wide variety of proteins, that include ion channels, G-protein coupled receptors (GPCRs), enzymes, and components of the cytoskeleton. This confers-light sensitivity to these proteins and effectively turns them into photoreceptors. In addition to this, synthetic photoswitches have been incorporated into lipids that are involved in cellular signaling or determine the biophysical properties of membranes. Once established, our synthetic photosensitive systems can be applied cells that are involved in downstream visual processing, such as bipolar cells, amacrine cells or retinal ganglion cells. If these cells can be made artificially light-sensitive, some level of vision could be restored in patients whose natural photoreceptor cells are either partially or completely lost.

The results of CARV show that this should be possible. Following a broad approach that involved almost a dozen of different receptor proteins, and dozens of associated synthetic photoswitches we have been able to restore visual function in blind animals. Indeed, our strategy has not only worked with retinal ganglion cells but also with bipolar cells and amacrine cells. The data obtained so far in different animal models and preliminary toxicology studies indicate that photopharmacological attempts to restore vision will work in humans. The new chemical tools that we have developed could be clinically applicable beyond vision restoration. They could be also used, for instance, to alleviate pain, or fight diabetes and cancer with the precision that only light provides. As such, we see CARV also as an important contribution to the development of precision medicine.