Restoring visual function to blind mice with an ion channel photoswitch
Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are degenerative blinding diseases caused by the death of rods and cones, leaving the remainder of the visual system intact but largely unable to respond to light. We have shown that, AAQ, a synthetic small molecule photoswitch, can restore light sensitivity to the retina and behavioral responses in vivo in mouse models of RP without exogenous gene delivery. Brief application of AAQ bestows prolonged light sensitivity on multiple types of retinal neurons, resulting in synaptically amplified responses and center-surround antagonism in arrays of retinal ganglion cells (RGCs). Intraocular injection of AAQ restores the pupillary light reflex (video) and locomotory light avoidance responses in mice lacking retinal photoreceptors, indicating reconstitution of light signaling to brain circuits. AAQ and related photoswitch molecules present a new drug strategy for restoring retinal function in degenerative blinding diseases. (Polosukhina et al., Neuron, 2012)
Over the past year, our focus has shifted to DENAQ, a new photoswitch with 4 favorable properties as compared to AAQ: 1) DENAQ photoswitches at a longer wavelengths (450-500 nm) as compared to AAQ (375-395 nm), 2) DENAQ photoswitching requires ~50-fold less intense light, 3) DENAQ rapidly “turns itself” off, allowing rapid repeated stimulation of the retina, 4) DENAQ persists for 3 days after intravitreal injection, >6 times longer than AAQ. These features make DENAQ a leading drug candidate for therapeutic vision restoration in RP. With this in mind, our aims are this year are: 1) initiate studies involving long-term delivery of DENAQ in mice with a polymer-encapsulated drug delivery system (collaboration with Erin Lavik, CWRU), 2) test the safety/toxicity of DENAQ during long-term delivery, 3) test the long-term efficacy of DENAQ in restoring retinal light sensitivity ex vivo and light-elicited behavior in vivo (collaboration with Russ Van Gelder, UW) 4) carry out studies to better understand the mechanism of DENAQ action on RGC ion channels, 5) carry out studies to understand the receptive field properties of RGCs in blind retinas treated with DENAQ.