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Qi Lu, Tushar H. Ganjawala, Gary W Abrams, Zhuo-Hua Pan; Retinal ganglion cell targeting is more efficient than bipolar cell targeting for optogenetic vision restoration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2590.
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© ARVO (1962-2015); The Authors (2016-present)
Optogenetics is a promising approach to restoring vision after photoreceptor degeneration. Multiple retinal cell-type specific targeting strategies have been reported. Especially, retinal bipolar cell (BC) targeting has been commonly thought to have advantages over retinal ganglion cell (RGC) targeting. However, the functional outcomes of these two different targeting strategies remain to be examined. In this study, we evaluated the efficacy of RGC versus BC targeting in a transgenic blind mouse model by in vitro electrophysiological recordings and animal behavioral tests.
The expression of a CoChR mutant, CoChR-L112C, fused to GFP in RGCs and in BCs were driven by CAG promoter and an improved mGluR6 promoter, respectively. The expression was delivered by AAV2.7m8 vectors with a Y444F capsid mutation via intravitreal administration. Experiments were performed in a triple knock-out (TKO), Gnat1-/-Cnga3-/-Opn4-/-, blind mouse model that lacks optomotor response (OMR) and apparent photoreceptor degeneration. OMR was examined using a LED-based homemade optomotor system. Multi-electrode array recordings in retinal whole-mounts were performed to examine CoChR-mediated light response properties of RGCs.
Restoration of OMR was observed in TKO mice with both RGC- and BC-targeting. The ability to elicit OMR was dependent on light intensity as well as grating frequency. In both cases, the most light-sensitive grating frequency was ~0.042 cycles/degree. However, the threshold light intensities required to elicit OMR at all examined grating frequencies were about 10x lower in RGC targeting than in BC targeting. Also, a much lower threshold light intensity was required to elicit spike activities of RGCs in RGC targeting than that in BC targeting.
Optogenetic gene therapy is much more efficient in RGC targeting than in BC targeting in a blind mouse model. Our results suggest that RGC targeting could be a preferable strategy for optogenetic vision restoration.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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