A nonhuman primate model of inherited retinal disease

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 C Yiu, J. Timothy Stout, Yijun Huang, Christopher J Murphy, Jeffrey A Roberts, Kota N. Gopalakrishna, Kimberly Boyd, Nikolai O. ArtemyevJeffrey Rogers, Sara M Thomasy

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)863-874
Number of pages12
JournalJournal of Clinical Investigation
Volume129
Issue number2
DOIs
StatePublished - Feb 1 2019

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Retinal Diseases
Color Vision Defects
Primates
Light Signal Transduction
Retinal Degeneration
Retinitis Pigmentosa
Electrophysiology
Vision Disorders
Felidae
Cyclic GMP
Missense Mutation
Blindness
Retina
Canidae
Rodentia
Catalytic Domain
Therapeutics
Animal Models
Messenger RNA
Enzymes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

A nonhuman primate model of inherited retinal disease. / 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 C; Stout, J. Timothy; Huang, Yijun; Murphy, Christopher J; Roberts, Jeffrey A; Gopalakrishna, Kota N.; Boyd, Kimberly; Artemyev, Nikolai O.; Rogers, Jeffrey; Thomasy, Sara M.

In: Journal of Clinical Investigation, Vol. 129, No. 2, 01.02.2019, p. 863-874.

Research output: Contribution to journalArticle

Moshiri, A, Chen, R, Kim, S, Harris, RA, Li, Y, Raveendran, M, Davis, S, Liang, Q, Pomerantz, O, Wang, J, Garzel, L, Cameron, A, Yiu, GC, Stout, JT, Huang, Y, Murphy, CJ, Roberts, JA, Gopalakrishna, KN, Boyd, K, Artemyev, NO, Rogers, J & Thomasy, SM 2019, 'A nonhuman primate model of inherited retinal disease', Journal of Clinical Investigation, vol. 129, no. 2, pp. 863-874. https://doi.org/10.1172/JCI123980
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 C ; Stout, J. Timothy ; Huang, Yijun ; Murphy, Christopher J ; Roberts, Jeffrey A ; Gopalakrishna, Kota N. ; Boyd, Kimberly ; Artemyev, Nikolai O. ; Rogers, Jeffrey ; Thomasy, Sara M. / A nonhuman primate model of inherited retinal disease. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 2. pp. 863-874.
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AU - Chen, Rui

AU - Kim, Soohyun

AU - Harris, R. Alan

AU - Li, Yumei

AU - Raveendran, Muthuswamy

AU - Davis, Sarah

AU - Liang, Qingnan

AU - Pomerantz, Ori

AU - Wang, Jun

AU - Garzel, Laura

AU - Cameron, Ashley

AU - Yiu, Glenn C

AU - Stout, J. Timothy

AU - Huang, Yijun

AU - Murphy, Christopher J

AU - Roberts, Jeffrey A

AU - Gopalakrishna, Kota N.

AU - Boyd, Kimberly

AU - Artemyev, Nikolai O.

AU - Rogers, Jeffrey

AU - Thomasy, Sara M

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