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.

The primate model for understanding and restoring vision

“…The genus diversified ∼5 million years ago and includes over 20 species that share >90% DNA sequence similarity and highly conserved protein sequences with humans. Moreover, humans and macaques share susceptibility genes for AMD and genotype-phenotype correlations for rare forms of inherited retinal diseases like achromatopsia (9) and retinitis pigmentosa (10). Old World monkeys such as rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis) are probably the best models for the study of ocular diseases (11).…”

“…Old World monkeys such as rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis) are probably the best models for the study of ocular diseases (11). However, due to the low prevalence of spontaneous disease, only a few animals are affected in even the largest research colonies, and their disease phenotypes have been long ignored (9). Reduction in the cost of DNA sequencing has revealed the amount of functional genetic variation in rhesus macaque research colonies and allowed broad surveys of genetic mutations that display a disease phenotype (12).…”

“…Unfortunately, there are only a few NHP models of macular disease. Examples of individual NHPs with validated inherited retinal disease have been described (44)(45)(46), but the genetic origin is known for only one rare form of achromatopsia (9). These animals, with all of the characteristic signs, symptoms, and functional deficits of phosphodiesterase 6C (PDE6C)-related achromatopsia, will be decisive in the development of gene or cell therapies targeting the fovea.…”

“…In the absence of representative genetic models of these conditions in NHPs, most of the clinical trials followed regulatory safety and toxicity studies on healthy NHPs. However, it is perhaps in inherited cone dystrophies that an NHP model will provide the most accurate readouts, with the emergence of a model for testing gene therapies directed toward PDE6C supplementation (9). Such work may allow comparison of outcomes using a model with identical genotypes/phenotypes to humans and also lead to gene replacement studies that have already restored cone cell function in mouse models with CNGB3 achromatopsia (80)(81)(82), as well as canine and sheep models of achromatopsia with mutations in CNGA3 (83,84).…”

Blinded by the light: a nonhuman primate model of achromatopsia

“…Several groups have shown remarkable improvement in cone function using adeno-associated virus-mediated (AAVmediated) gene therapy in murine (11-13), canine (8), and sheep (14) models of the achromatopsia (7). The animals exhibited behavioral changes, including impaired navigation and tactile exploration of new environments that was worse in bright conditions such as outdoor daylight, reminiscent of the human disease.…”