Development and application of novel membrane-targeted photoswitches for restoration of the physiological retinal processing in Retinitis pigmentosa (LIGHTSWITCH)

One of the most prevalent causes of inherited bilateral blindness is the progressive degeneration of photoreceptors in Retinitis pigmentosa (RP). Various therapeutic approaches, including drugs, gene therapy or stem cells, have been unsuccessful in the most advanced forms of RP. This encouraged many groups to restore visual functions using electrical stimulation of the spared retinal network with retinal prostheses. However, these electronic devices cover only a tiny part of the retina and do not restore the complex processing of visual information of the inner retina, resulting in poor performances. We propose an entirely new concept for RP therapy whereby a device is replaced by an injectable light-sensitive “paint” made of photochromic molecules (Ziapins) that incorporate in the membrane of the surviving retinal neurons and exert a bidirectional modulation of excitability, inhibiting neurons in the dark and exciting them in the light. Not only Ziapins can recreate the mosaic of ON and OFF cells that generates visual acuity and contrast sensitivity, but they have the potential of permeate large retinal areas after a minimally invasive injection, thus recreating a physiological field of view. The proposed first application of Ziapin to the eye and RP retinal degeneration stems from previous results showing that these compounds are not toxic to the nervous tissue and are active in modulating the electrical activity of human neurons. The project will allow to exploit these promising results in an experimental model of RP in view of the final transfer of this strategy to RP patients.