A nonhuman primate model of inherited retinal disease.

TitleA nonhuman primate model of inherited retinal disease.
Publication TypeJournal Article
Year of Publication2019
AuthorsMoshiri, A, Chen, R, Kim, S, Harris, RA, Li, Y, Raveendran, M, Davis, S, Liang, Q, Pomerantz, O, Wang, J, Garzel, L, Cameron, A, Yiu, G, J Stout, T, Huang, Y, Murphy, CJ, Roberts, J, Gopalakrishna, KN, Boyd, K, Artemyev, NO, Rogers, J, Thomasy, SM
JournalJ Clin Invest
Date Published2019 Feb 01
KeywordsAmino Acid Substitution, Animals, Color Vision Defects, Cone Dystrophy, Cyclic Nucleotide Phosphodiesterases, Type 6, Disease Models, Animal, Eye Proteins, Female, HEK293 Cells, Humans, Macaca mulatta, Male, Mutation, Missense, Retinitis Pigmentosa

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.

Alternate JournalJ Clin Invest
PubMed ID30667376
PubMed Central IDPMC6355306
Grant ListS10 OD023469 / OD / NIH HHS / United States
R01 EY026045 / EY / NEI NIH HHS / United States
U24 EY029904 / EY / NEI NIH HHS / United States
R24 RR032329 / RR / NCRR NIH HHS / United States
P30 EY012576 / EY / NEI NIH HHS / United States
R24 OD011173 / OD / NIH HHS / United States
P51 OD011107 / OD / NIH HHS / United States
K08 EY027463 / EY / NEI NIH HHS / United States
R01 EY010843 / EY / NEI NIH HHS / United States
P30 EY002520 / EY / NEI NIH HHS / United States
K08 EY021142 / EY / NEI NIH HHS / United States

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