A nonhuman primate model of inherited retinal disease

• Published in: The Journal of clinical investigation Vol. 129; no. 2; pp. 863 - 874
• Main Authors: Moshiri, Ala, Chen, Rui, Kim, Soohyun, Harris, R Alan, Li, Yumei, Raveendran, Muthuswamy, Davis, Sarah, Liang, Qingnan, Pomerantz, Ori, Wang, Jun, Garzel, Laura, Cameron, Ashley, Yiu, Glenn, Stout, J Timothy, Huang, Yijun, Murphy, Christopher J, Roberts, Jeffrey, Gopalakrishna, Kota N, Boyd, Kimberly, Artemyev, Nikolai O, Rogers, Jeffrey, Thomasy, Sara M
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-02-2019
• Subjects: Amino Acid Substitution; Animal experimentation; Animal models; Animals; Behavior; Biomedical research; Blindness; Color blindness; Color Vision Defects - enzymology; Color Vision Defects - genetics; Color Vision Defects - pathology; Cone Dystrophy - enzymology; Cone Dystrophy - genetics; Cone Dystrophy - pathology; Cyclic GMP; Cyclic guanosine monophosphate; Cyclic Nucleotide Phosphodiesterases, Type 6 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 6 - metabolism; Disease; Disease Models, Animal; DNA sequencing; Electrophysiology; Enzymes; Eye Proteins - genetics; Eye Proteins - metabolism; Female; Genes; Genetic aspects; Genome editing; Genomes; Genomics; HEK293 Cells; Humans; Localization; Macaca mulatta; Male; Messenger RNA; Missense mutation; mRNA; Mutation; Mutation, Missense; Photoreceptors; Phototransduction; Primates; Proteins; Retina; Retinal degeneration; Retinal diseases; Retinitis; Retinitis pigmentosa; Retinitis Pigmentosa - enzymology; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - pathology; RNA; Signal transduction; Stem cells; Visual impairment; United States > US; California; Genetic diseases; Ophthalmology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI123980

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.