A nonhuman primate model of inherited retinal disease
Ala Moshiri, … , Jeffrey Rogers, Sara M. Thomasy
Ala Moshiri, … , Jeffrey Rogers, Sara M. Thomasy
Published February 1, 2019; First published January 22, 2019
Citation Information: J Clin Invest. 2019;129(2):863-874. https://doi.org/10.1172/JCI123980.
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Categories: Research Article Ophthalmology

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 3

Noninvasive retinal imaging of affected visually impaired rhesus macaques shows evidence of slowly progressive macular atrophy consistent with achromatopsia.

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Noninvasive retinal imaging of affected visually impaired rhesus macaque...
Color fundus photography (A–E), fluorescein angiography (F–J), and fundus autofluorescence (K–N) were obtained in unaffected control and affected visually impaired subjects. An example of a control subject is shown (A, F, K; age 9 years), demonstrating normal posterior pole findings. The fundus photos of affected animals show a largely normal macular appearance, but with prominent foveal pigmentation (B–E). The fluorescein angiogram in affected subjects demonstrated normal retinal vasculature at ages 2 (G) and 3 years (H), but the appearance of a bullseye pattern of foveal staining surrounded by parafoveal hypofluorescence was evident by age 4 years (I), and even more obvious by age 11 years (J). Fundus autofluorescence shows normal macular autofluorescence at age 2 years (L). At age 3 years (M) there is prominent foveal hyperautofluorescence, and development of an annulus of hypoautofluorescence centered on the fovea by age 11 years (N) which corresponds to the bullseye pattern seen on fluorescein angiography. Imaging software failure precluded fundus autofluorescence in the 4-year-old subject. Color fundus images were taken with a 50 degree lens. Fluorescein angiography and fundus autofluorescence images were taken with a Heidelberg Spectralis device using the default image size of 30 degrees.