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Home , Achromatopsia, Jean Bennett, Photophobia

The Journal of Clinical Investigation COMMENTARY Blinded by the : a nonhuman model of

Katherine E. Uyhazi and Jean Bennett Center for Advanced Retinal and Ocular Therapeutics, F.M. Kirby Center for Molecular , 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 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 , 10% of the population is com- this condition. Patients are encouraged to pletely color blind. Fishermen fish at night Fifty wear visors and -tinted or con- because they can see better in the moon- There are two main forms of achromatop- tact lenses to minimize in light. Affected families stay in cabins sia in humans: complete achromatopsia bright environments. There are even wear- during the day and wear and (rod or total color blind- able devices that allow patients to “hear squint when they venture outside. Tropical ness), an autosomal recessive disease ” 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 and 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 in red- 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 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 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 , 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 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 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 , and severe photophobia due to inherited defects in cone photoreceptors. (A and B) Only 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 , foveal thinning, and reasons. First, the underlying 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 (AAV- in healthy tissue. types of achromatopsia in humans, this mediated) gene therapy in murine (11–13), This model also provides a platform model may lend insight into the pathophys- canine (8), and sheep (14) models of the to test neuroprotective agents and cell-

514 jci.org Volume 129 Number 2 February 2019 The Journal of Clinical Investigation COMMENTARY based therapies designed to slow, prevent, outstanding questions in the field. What 5. Alfaro A, Bernabeu Á, Agulló C, Parra J, Fernán- or reverse death. Since are the ideal cells to transplant? Can trans- dez E. colors: an example of brain plas- ticity. Front Syst Neurosci. 2015;9:56. these therapies are not gene specific, the planted precursors differentiate in vivo 6. Roosing S, Thiadens AA, Hoyng CB, Klaver broader utility of the model lies in test- into functional cones? Do transplanted CC, den Hollander AI, Cremers FP. Causes and ing strategies to treat photoreceptor loss photoreceptors form appropriate synaptic consequences of inherited cone disorders. Prog in general. Even in rod-specific diseases, connections in degenerated retina, and Retin Eye Res. 2014;42:1–26. which account for the majority of retinal how are these processes regulated? Is func- 7. Moshiri A, et al. A nonhuman primate model of inherited retinal disease. J Clin Invest. degenerative conditions, the ultimate loss tional improvement due to cellular inte- 2019;129(2):863–874. of visual acuity in human blinding dis- gration, fusion, or to soluble neurotrophic 8. Komáromy AM, et al. Gene therapy rescues cone orders results from the associated death factors? Answers to these questions may function in congenital achromatopsia. Hum Mol of cone photoreceptors. Therefore, this further our understanding of achromatop- Genet. 2010;19(13):2581–2593. model may be useful to understand rod- sia and bring us one step closer to develop- 9. Mühlfriedel R, et al. AAV-mediated gene sup- plementation therapy in achromatopsia type 2: cone interactions and to test cone protec- ing better treatments for retinal diseases. preclinical data on therapeutic time window and tive strategies such as rod-derived cone long-term effects. Front Neurosci. 2017;11:292. viability factor (RdCVF) (18). If even a Acknowledgments 10. Aboshiha J, et al. A prospective longitudinal small percentage of cones could be pre- This work is supported by the Center for study of retinal structure and function in served in humans, a significant improve- Retinal Ocular Therapeutics, University achromatopsia. Invest Ophthalmol Vis Sci. 2014;55(9):5733–5743. ment in vision is possible. However, not of Pennsylvania Perelman School of Med- 11. Alexander JJ, et al. Restoration of cone vision all treatments that improve cone function icine, Research to Prevent Blindness, the in a mouse model of achromatopsia. Nat Med. may translate into therapeutic targets. Brenda and Matthew Shapiro Steward- 2007;13(6):685–687. For example, ciliary neurotrophic factor ship, the Robert and Susan Heidenberg 12. Carvalho LS, et al. Long-term and age- (CNTF) can improve cone function in Investigative Research Fund for Ocular dependent restoration of visual function in a a canine model of CNGB3-associated Gene Therapy, the Paul and Evanina Bell mouse model of CNGB3-associated achroma- topsia following gene therapy. Hum Mol Genet. achromatopsia, but results in a decline in Mackall Foundation Trust, The Pennsyl- 2011;20(16):3161–3175. rod function and no improvement in cone vania Lions Sight Conservation, and the 13. Pang JJ, et al. AAV-mediated cone rescue function when expressed intravitreally in F.M. Kirby Foundation. We are grateful to in a naturally occurring mouse model human patients (19). Adaptive optics scan- Tomas S. Aleman for helpful comments of CNGA3-achromatopsia. PLoS One. ning light ophthalmoscopy, in which single and for reviewing this commentary. 2012;7(4):e35250. 14. Banin E, et al. Gene augmentation therapy photoreceptor cells can be imaged in vivo, restores retinal function and visual behavior in may be useful to identify the earliest struc- Address correspondence to: Jean Bennett, a sheep model of CNGA3 achromatopsia. Mol tural changes in the retina, explore the Center for Advanced Retinal and Ocular Ther. 2015;23(9):1423–1433. interactions between rods and cones, and Therapeutics, Department of Ophthal- 15. Michalakis S, et al. Restoration of cone vision in –/– measure a response to treatment. mology, Perelman School of Medicine, the CNGA3 mouse model of congenital com- plete lack of cone photoreceptor function. Mol Lastly, induced pluripotent stem cell– 310 Stellar-Chance Laboratories, Univer- Ther. 2010;18(12):2057–2063. derived (iPSC-derived) photoreceptor sity of Pennsylvania, 422 Curie Boulevard, 16. Hassall MM, Barnard AR, MacLaren RE. Gene transplantation­ experiments and CRISPR- Philadelphia, Pennsylvania 19104, USA. therapy for . Yale J Biol Med. based gene editing are both promising ave- Phone: 215.898.0915; Email: jebennet@ 2017;90(4):543–551. nues of retinal regeneration research that pennmedicine.upenn.edu. 17. Ye GJ, et al. Cone-specific promoters for gene therapy of achromatopsia and other retinal are well suited to test in such a naturally diseases. Hum Gene Ther. 2016;27(1):72–82. 1. Sacks O. The Island of the Colorblind. New York, occurring genetic model of photoreceptor 18. Sahel JA, Léveillard T. Maintaining cone function New York, USA: Vintage Books; 1996. dysfunction. Much of the ocular regener- in rod-cone dystrophies. In: Ash J, Anderson R, 2. Winick JD, Blundell ML, Galke BL, Salam AA, ation field has moved toward using iPSCs LaVail M, Bowes Rickman C, Hollyfield J, Grimm Leal SM, Karayiorgou M. Homozygosity map- as a source of retinal progenitor cells. It has C, eds. Retinal Degenerative Diseases. Advances in ping of the achromatopsia locus in the Pingela- Experimental Medicine and . Vol 1074. New been historically difficult to generate fully pese. Am J Hum Genet. 1999;64(6):1679–1685. York, New York, USA: Springer; 2018:499–509. differentiated cells in vitro for use in trans- 3. Remmer MH, Rastogi N, Ranka MP, Ceisler EJ. 19. Zein WM, et al. CNGB3-achromatopsia clini- plantation experiments. However, it is Achromatopsia: a review. Curr Opin Ophthalmol. cal trial with CNTF: diminished rod pathway now possible to generate iPSC-derived ret- 2015;26(5):333–340. responses with no evidence of improvement 4. Hirji N, Aboshiha J, Georgiou M, Bainbridge inal organoids that contain light-sensitive in cone function. Invest Ophthalmol Vis Sci. J, Michaelides M. Achromatopsia: clinical 2014;55(10):6301–6308. photoreceptor precursors with early outer features, molecular genetics, animal models 20. Zhong X, et al. Generation of three-dimensional segments (20). Cell transplantation exper- and therapeutic options. Ophthalmic Genet. retinal tissue with functional photoreceptors iments in this model could address several 2018;39(2):149–157. from human iPSCs. Nat Commun. 2014;5:4047.

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