A nonhuman primate model of inherited retinal disease
Ala Moshiri, … , Jeffrey Rogers, Sara M. Thomasy
Ala Moshiri, … , Jeffrey Rogers, Sara M. Thomasy
Published January 22, 2019
Citation Information: J Clin Invest. 2019;129(2):863-874. https://doi.org/10.1172/JCI123980.
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A nonhuman primate model of inherited retinal disease

Abstract

Inherited retinal degenerations are a common cause of untreatable blindness worldwide, with retinitis pigmentosa and cone dystrophy affecting approximately 1 in 3500 and 1 in 10,000 individuals, respectively. A major limitation to the development of effective therapies is the lack of availability of animal models that fully replicate the human condition. Particularly for cone disorders, rodent, canine, and feline models with no true macula have substantive limitations. By contrast, the cone-rich macula of a nonhuman primate (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders that are predictive of human conditions, are necessary to more efficiently advance new therapies for patients. We have identified 4 related NHPs at the California National Primate Research Center with visual impairment and findings from clinical ophthalmic examination, advanced retinal imaging, and electrophysiology consistent with achromatopsia. Genetic sequencing confirmed a homozygous R565Q missense mutation in the catalytic domain of PDE6C, a cone-specific phototransduction enzyme associated with achromatopsia in humans. Biochemical studies demonstrate that the mutant mRNA is translated into a stable protein that displays normal cellular localization but is unable to hydrolyze cyclic GMP (cGMP). This NHP model of a cone disorder will not only serve as a therapeutic testing ground for achromatopsia gene replacement, but also for optimization of gene editing in the macula and of cone cell replacement in general.

Authors

Ala Moshiri, Rui Chen, Soohyun Kim, R. Alan Harris, Yumei Li, Muthuswamy Raveendran, Sarah Davis, Qingnan Liang, Ori Pomerantz, Jun Wang, Laura Garzel, Ashley Cameron, Glenn Yiu, J. Timothy Stout, Yijun Huang, Christopher J. Murphy, Jeffrey Roberts, Kota N. Gopalakrishna, Kimberly Boyd, Nikolai O. Artemyev, Jeffrey Rogers, Sara M. Thomasy

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Figure 2

Quantitative comparison of electroretinography shows absent cone-mediated and subnormal rod-mediated amplitudes.

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Quantitative comparison of electroretinography shows absent cone-mediate...
The absolute value of the ERG amplitudes (μV: microvolts) of both a- and b-waves from control and affected subjects was quantified and is graphically depicted. Under dark adapted conditions, using a 0.01 cd•s/m2 stimulus, the rod system was tested and found to be subnormal in affected subjects when compared with unaffected controls. The rod and cone combined ERG, measured under dark adapted conditions using a 3.0 cd•s/m2 stimulus, showed moderately reduced responses in affected subjects compared with controls. The cone-mediated pathway was tested in the light-adapted state using a single flash 3.0 cd•s/m2 stimulus, and also a flicker (30 Hz) with the same stimulus and showed virtually undetectable responses in the affected subjects (n = 4 in each group, *P < 0.05, Student’s t test). Whiskers represent minimum and maximum. Boxes represent interquartile range. Line represents the median, and dots represent data points.