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S. Nusinowitz, W.H. Ridder, III, J.J. Pang, B. Chang, W.W. Hauswirth, J.R. Heckenlively; Cortical Visual Function Following Retinal Rescue in a Mouse Model of Lebers Congenital Amaurosis (LCA) . Invest. Ophthalmol. Vis. Sci. 2006;47(13):845.
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© ARVO (1962-2015); The Authors (2016-present)
To examine intensity, spatial and temporal response functions at the level of the visual cortex after gene therapy to rescue retinal structure and function in a naturally–occurring mouse model of LCA.
The rd12 mutant mouse, originally discovered at the Jackson laboratories, and a natural mutant of LCA, was used in these studies. A serotype 5 recombinant adeno–associated virus (rAAV) carrying a normal human RPE65 cDNA was injected sub–retinally at postnatal day 18 (P18) and at 6– (6M) and 7– (7M) months of age. Retinal and cortical visual function was assayed with the electroretinogram (ERG) and the visual evoked cortical potential (VECP), respectively. Rod and cone visual function was characterized with intensity, spatial and temporal tuning functions. Visual acuity was measured with the sweep VECP.
Rod ERG Vmax amplitudes were 51% and 32% of normal when treated at P18 and at 6M – 7M, respectively. VEP responses were correlated with the extent of retinal rescue; VEP Vmax amplitudes were 56% and 36% of normal for the same mice and ages. Rod– ERG temporal response functions were of similar shape compared to normal but rod amplitudes were lower, resulting in a lower critical fusion frequency (CFF). Cone ERG temporal response functions were within normal limits for P18 and 6M, except at the highest temporal frequencies where selective loss was apparent. Rod VEP response functions was similar to normal mice but shifted to lower amplitudes, consistent with predictions based on retinal responsivity. Cone VEPs were significantly lower at P18, barely detectable at 6M, and non–detectable at 7M. Sweep VEP acuity was significantly lower than normal at all ages.
Consistent with prior studies, early gene replacement therapy resulted in better retinal rescue. Cortical visual function generally corresponded to the degree of retinal rescue for many aspects of visual function when treatment occurred at an early age, suggesting relatively intact visual pathway function. However, selective loss in VECP responses at higher temporal and spatial frequencies was apparent in mice treated at an older age, consistent with visual pathway dysfunction in these mice. These results provide further support that early treatment will have the most hope for optimal visual abilities.
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