Authors:
N. Caporale, K. D. Kolstad, T. Huang, D. Dalkara, D. Trauner, R. H. Kramer, Y. Dan, E. Y. Isacoff, & J. G. Flannery
Summary:
Retinitis pigmentosa refers to a heterogeneous group of inherited diseases in which genetic mutations result in progressive photoreceptor degeneration. Without photoreceptor activity, visual processing cannot take place, despite the fact that second and third order retinal neurons remain functional. These diseases currently cause severe visual deficits in one of every 3,000 individuals. Currently, there are no approved therapies to slow the progression of this disease, or stop photoreceptor cell death. An alternative therapy is to restore light responsiveness to a retina devoid of photoreceptors by expressing light-activated channels in surviving neurons. We used intravitreal injection of adeno-associated virus serotype 2 (AAV2) to deliver the engineered light activated glutamate receptor, LiGluR, to retinal ganglion cells (RGCs) in the rd1 mouse model of blinding retinal degeneration, which lacks photoreceptors at the late stages of the disease. Single-unit recordings from retinal wholemounts show that LiGluR successfully imparts light sensitivity onto RGCs, allowing for precise and reversible light-mediated control of spiking activity. Local field recordings in anesthetized mice were used to characterize LiGluR-mediated visual responses at the cortical level in response to brief (50ms) and long (300ms) pulses of full-field illumination. Visual responses were maximal at ~380nm (corresponding to the peak wavelength sensitivity of LiGluR), and could be obtained even 48 hours post-injection of the photoswitch. Peak LiGluR-mediated cortical field potentials in response to a 300ms full-field flash (-371.5 ± 36 μV, n=13) were significantly larger (p<0.0001, Wilcoxon sign rank test) than those mediated by Channelrhodopsin2 (-61.7 ± 12.3 μV,n=6). These results suggest that LiGluR is a promising candidate for therapeutics aimed at restoring visual function to patients in late stage retinal degeneration.
Source:
Presented at Neuroscience 2009, the annual meeting of the Society for Neuroscience. Scientific Presentation: Wednesday, Oct. 21, 3:15–3:30 p.m., Room N426