期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 2, 页码 863-874出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI123980
关键词
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资金
- NIH [U24 EY029904, K08 EY021142, P30 EY12576, K08 EY027463]
- Barr Retinal Research Foundation
- CNPRC Base Grant from the NIH Office [OD011107]
- NIH from the National Eye Institute [R01 EY026045, R01 EY10843, R24-OD11173]
- Knights Templar Eye Foundation
- School of Veterinary Medicine, University of California, Davis
- [S10OD023469]
- [P30 EY002520]
- NATIONAL EYE INSTITUTE [P30EY002520] Funding Source: NIH RePORTER
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.
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