The Journal of Clinical Investigation COMMENTARY Blinded by the light: a nonhuman primate model of achromatopsia Katherine E. Uyhazi and Jean Bennett Center for Advanced Retinal and Ocular Therapeutics, F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA. sitely light-sensitive rod photoreceptors for both night- and daytime vision. How- Achromatopsia is an inherited retinal degeneration characterized by the ever, rods are specialized to function well loss of cone photoreceptor function. In this issue of the JCI, Moshiri et in dimly lit conditions, but are too sensitive al. characterize a naturally occurring model of the disease in the rhesus to work efficiently in bright light, resulting macaque caused by homozygous mutations in the phototransduction in glare. Rods also have low spatial resolu- enzyme PDE6C. Using retinal imaging, and electrophysiologic and tion, leading to decreased acuity. biochemical methods, the authors report a clinical phenotype nearly There are currently six known caus- identical to the human condition. These findings represent the first genetic ative genes of achromatopsia, almost all of nonhuman primate model of an inherited retinal disease, and provide an which are components of the phototrans- ideal testing ground for the development of novel gene replacement, gene duction cascade in cone photoreceptors editing, and cell replacement therapies for cone dystrophies. (3). Approximately 75% of affected individ- uals have mutations in cyclic nucleotide- gated channel beta 3 or alpha 3 (CNGB3 or CNGA3), while the remainder of cases are caused by mutations in the remaining four Color blindness vivors, one of whom was a heterozygous genes (GNAT2, PDE6C, PDE6H, or ATF6) On the remote South Pacific island of carrier of the disease (2). (3, 4). There is currently no treatment for Pingelap, 10% of the population is com- this condition. Patients are encouraged to pletely color blind. Fishermen fish at night Fifty shades of gray wear visors and red-tinted glasses or con- because they can see better in the moon- There are two main forms of achromatop- tact lenses to minimize photophobia in light. Affected families stay in cabins sia in humans: complete achromatopsia bright environments. There are even wear- during the day and wear sunglasses and (rod monochromacy or total color blind- able devices that allow patients to “hear squint when they venture outside. Tropical ness), an autosomal recessive disease colors” by converting color information sunlight is more of a curse than a paradise in which all three subtypes of cones are into sound waves (5), but to date there are to these inhabitants, as bright light turns absent, and incomplete achromatopsia, no approved therapies that improve visual their black and white world into an over- a milder form in which one or more cone acuity or color sensitivity. exposed blur that produces debilitating subtype has residual function. Unlike glare. Immortalized by Oliver Sacks in red-green color deficiency that affects up Monkey see, monkey do his 1997 book The Island of the Colorblind to eight percent of the male population, Much of our understanding of the patho- (1), the condition maskun — meaning “not achromatopsia results in severely reduced physiology of achromatopsia comes from see,” now known as achromatopsia — is visual acuity that often impairs the quality small animal models of the disease, an inherited retinal disease resulting in of life. Patients with complete achroma- including Cnga3- and Cngb3-KO mice (6). the loss of function of cone photorecep- topsia typically present with decreased One major limitation of these models, tors. While achromatopsia affects approx- visual acuity (~20/200), lack of color however, is that rodents have neither a spe- imately 1 in 50,000 people worldwide, its vision, abnormal repetitive eye move- cialized region of high-resolution vision extremely high prevalence in Pingelap can ments, and severe photophobia (Figure 1). (i.e., fovea) nor a cone photoreceptor– be traced to a typhoon in 1775 that deci- Because all three cone subtypes are dys- enriched macula, and thus do not accu- mated the population and left only 20 sur- functional, the retina relies on the exqui- rately represent the anatomy or function of the human central retina. The nonhu- man primate eye closely resembles the Related Article: p. 863 human eye, but research efforts have been limited by the lack of available disease Conflict of interest: JB is a scientific (non–equity-holding) founder of Spark Therapeutics, and founder of GenSight Biologics, models and expense. Limelight Bio, and Perch Therapeutics. She serves on scientific advisory boards for Acouos and Odylia Therapeutics and is the Prin- In this issue of the JCI, Moshiri and cipal Investigator of sponsored research agreements from Limelight Bio and Biogen. JB is a coinventor on a patent for a method to colleagues describe four related rhe- treat or slow the development of blindness, but waived any financial interest in this technology in 2002. JB is a coinventor on sev- eral other patents related to retinal gene therapy applications, as follows: 10,155,794; 9,567,376; 9,433,688; 9,249,425; 9,896,665; sus macaques at the California Primate 8,147,823; 5,012,815; 20180369415; 20180369412; 20180153962; 20170319058; 201700143505; 20160263246. Research Center with visual impairment Reference information: J Clin Invest. 2019;129(2):513–515. https://doi.org/10.1172/JCI126205. and clinical findings consistent with jci.org Volume 129 Number 2 February 2019 513 COMMENTARY The Journal of Clinical Investigation Figure 1. Complete achromatopsia typically results in poor visual acuity, lack of color vision, and severe photophobia due to inherited defects in cone photoreceptors. (A and B) Only primates have a macula, the region of the central retina enriched in cones and containing the cone-only fovea. Thus, avail- ability of a nonhuman primate model will facilitate both basic research and interventional studies. achromatopsia (7). The animals exhibited iology of the more frequent CNGB3- and disease. Expression of a corrective copy of behavioral changes, including impaired CNGA3-associated disease. the gene improves retinal morphology, cone navigation and tactile exploration of new survival, inflammatory responses, electro- environments that was worse in bright con- An AAVenue towards a cure physiological testing, and cone-mediated ditions such as outdoor daylight, reminis- Achromatopsia represents an attractive tar- visual behavior (15). Subsequently, several cent of the human disease. They had a pig- get for gene therapy in humans for several phase I/II human trials are in progress for mentary maculopathy, foveal thinning, and reasons. First, the underlying genetics and CNGB3- and CNGA3-related disease (16). hyper- and hypoautofluorescent changes causative mutations of the disease have Interestingly, not all cone-specific promot- surrounding the fovea. Full-field scotopic been well characterized in multiple ani- ers that rescue cone function in small ani- and photopic ERG testing showed normal mal models of the disease. Second, cone mal models are effective in primates (17). rod responses and absent cone responses. cells remain physically present, albeit non- Therefore, the model reported by Moshiri Whole-genome shotgun sequencing re­­ functional, in patients with achromatop- et al. represents an invaluable resource for vealed homozygous missense mutations sia and can be targeted with cone-specific vector optimization and preclinical trial (R565Q) in the catalytic domain of the promoters. Third, since cones are densely testing. Since the macaque eye is relatively gene encoding cone phosphodiesterase concentrated in the central macula, subret- similar in size, structure, and immune envi- 6C (PDE6C), a key component of the cone inal delivery of a viral vector would easily ronment to the human eye, this naturally phototransduction cascade, which results encompass the entire region necessary for occurring disease model provides a rare in the expression of a catalytically inac- functional improvement in central vision. opportunity to test the toxicity and dosage tive protein in vitro. Although mutations Lastly, although gene therapy rescue in titration of clinical vectors, as well as the in PDE6C account for less than one per- other animal models of achromatopsia structural and functional rescue of cone cent of human achromatopsia (4), and this showed better outcomes in younger animals photoreceptor cells after gene therapy. It particular mutation has not been reported compared with older animals (8, 9), the dis- would be especially interesting to assess in humans, this model nonetheless rep- ease is relatively stationary in humans and the immunogenicity of AAV treatments in resents a significant advance in the field as shows no direct correlation with age or gen- these macaques, as the immunoprivileged it shares a nearly identical phenotype with otype (10), thus there may be a large win- status of the eye may be altered in inher- the human disease and provides a biolog- dow of opportunity for treatment. ited retinal conditions that involve retinal ically relevant model of cone-mediated Several groups have shown remark- cell death, remodeling, and subsequent visual loss. Given the phenotypic similari- able improvement in cone function using loss of the immune barriers normally found ties between the different molecular sub- adeno-associated virus–mediated