2012 Progress Report – Executive Summary
Progress on Translational Path
Our primary TPath is in restoration of vision. The efforts, which focused initially on genetic mouse models of retinitis pigmentosa (RP) have expanded to genetic models of RP in dogs and to irradiation-induced models in primate.
1) Mouse model. We have made significant progress with both the 2 component (photoswitch + targeted gene) and 1 component (photoswitch only) approaches to reanimating the blind retina following photoreceptor degeneration showing that light-activated glutamate receptors in surviving retinal ganglion cells or photoswitches for native K+ channels in surviving amacrine and retinal ganglion cells of mutant mouse models of RP can restore retinal, cortical, and behavioral responses to light.
2) Canine model. We added genetically blind canine RP models to the effort as large animal models that more closely represent human vision. Two aspects have been developed: viral gene delivery to RGCs and behavioral assessment in dog models of retinal degeneration. Two genetic models have been shown to be promising in behavioral assays.
3) Primate model. As an even better model of the human visual system, we have developed a macaque model of visual loss: 647 nm laser induced outer retinal degeneration that kills off photoreceptors and spares retinal ganglion cells. We developed AAVs that deliver genes to these RGCs via intravitreal injection—just as used in mouse. And we developed optical recording using genetically encoded sensors in awake-behaving animals as a complement to psychophysical assessment of vision.
Our second, minor Tpath is in pain, where we have made substantial progress in generating the first light-controlled Na+ channel blocker that is selectively picked up by pain-sensing neurons that are active.
Progress in the past year
Progress in the past year included 21 publications (including 1 each in Nature, Nature Cell Biology, Nature Chemistry, Nature Neuroscience and Nature Methods, as well as 2 in Neuron, 1 in Current Biology, 1 in Molecular Therapy and 1 in Cell Reports). In addition, there were several submitted papers, 1 patent application submitted and one patent awarded and several studies that are near completion. Several of these papers represent new collaborations within the NDC and several others represent new collaborations with outside labs that are beginning to use our technologies. Important among these for our translational path were:
a) The demonstration that both the 1 and 2 component systems can restore a simple visually guided behavior in a mouse model of RP;
b) The first light-gated GPCRs, which hold the promise of enhanced sensitivity to light due to natural amplification. c) The first light controlled analgesic.
d) The first evidence that optogenetic activation of a sub-class of inhibitory interneurons in the visual cortex can be used to sharpen feature selectivity and visual perception.
e) Several technical steps forward that make our chemical-opto-genetic approach to restoration of vision and treatment of pain more realistic.
Dissemination of information about our program was amplified through an additional 10 related papers as well as 29 presentations in major venues, including a symposium co-organized by co-PI John Flannery (along with Richard Masland) on “Optogenetic Therapies for Vision.” This meeting was sponsored by the Foundation Fighting Blindness at the Starr Conference Center of the Massachusetts Eye and Ear Infirmary, May 31 - June 1, 2012.
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