A spontaneous nonhuman primate model of inherited retinal degeneration
Wei Yi, Mingming Xu, Ying Xue, Yingxue Cao, Ziqi Yang, Lingli Zhou, Yang Zhou, Le Shi, Xiaomei Mai, Zehui Sun, Wenjie Qing, Yuying Li, Aolun Qing, Kaiwen Zhang, Lechun Ou, Shoudeng Chen, Elia J. Duh, Xialin Liu
Wei Yi, Mingming Xu, Ying Xue, Yingxue Cao, Ziqi Yang, Lingli Zhou, Yang Zhou, Le Shi, Xiaomei Mai, Zehui Sun, Wenjie Qing, Yuying Li, Aolun Qing, Kaiwen Zhang, Lechun Ou, Shoudeng Chen, Elia J. Duh, Xialin Liu
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Research Article Genetics Ophthalmology

A spontaneous nonhuman primate model of inherited retinal degeneration

Abstract

Inherited retinal degenerations (IRDs) are important causes of progressive, irreversible blindness. Hereditary macular diseases, in particular, are significant in their effect on the specialized, central cone photoreceptor–rich macula responsible for high resolution vision. Autosomal dominant Best vitelliform macular dystrophy (BVMD), caused by variants in the BEST1 gene, is one of the most common inherited macular dystrophies. Gene therapies have emerged as promising treatments for IRDs, but a lack of suitable animal models has hindered progress both in treatments and in understanding the mechanisms underlying macular diseases. Here, we report a Macaca fascicularis carrying a heterozygous potential pathogenic BEST1p.Q327E variant that disrupts the BEST1 ion channel by destabilizing the A195 helix, mirroring the structural perturbations seen in certain human pathological mutants. Longitudinal imaging over 2 years revealed progressive macular changes, including subfoveal cleft enlargement, lipid-rich deposit accumulation, retinal pigment epithelium (RPE) disruption, and central-to-peripheral photoreceptor degeneration, recapitulating early human BVMD pathology. Histopathology demonstrated diminished BEST1 expression, attenuation of the RPE-photoreceptor interface, and 2 distinct types of lipid deposits, including heretofore unappreciated cone mitochondrial-enriched lesions, highlighting selective cone mitochondria vulnerability. This is, to our knowledge, the first nonhuman primate model of inherited macular dystrophy, and it links BEST1 mutations, mitochondrial dysfunction, and progressive macular degeneration, offering new insights into BVMD pathophysiology and highlighting its utility for studying disease progression and potential therapeutic interventions.

Authors

Wei Yi, Mingming Xu, Ying Xue, Yingxue Cao, Ziqi Yang, Lingli Zhou, Yang Zhou, Le Shi, Xiaomei Mai, Zehui Sun, Wenjie Qing, Yuying Li, Aolun Qing, Kaiwen Zhang, Lechun Ou, Shoudeng Chen, Elia J. Duh, Xialin Liu

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Figure 4

Histopathologic analysis reveals typical pathogenic features of BVMD.

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Histopathologic analysis reveals typical pathogenic features of BVMD. (A...
(A) Bright field and immunostaining imaging showing neuroretina detachment from the RPE in the mutant fovea, forming a cleft with the accumulation of autofluorescent deposits within it. Autofluorescence was detected at 555 nm (red), and nuclei were stained with DAPI (blue). (B) Immunostaining for BEST1 protein (red) and RPE cell marker RPE65 (green), with nuclei stained with DAPI (blue). (C) DAPI staining highlights fragmented RPE nuclei in the mutant animal. Fragmented nuclei are indicated by red arrowheads, while normal nuclei are indicated by yellow arrowheads. Costaining with RPE65 was performed to identify the nuclei of RPE cells. (D) The density of RPE cells was significantly reduced in the fovea and parafoveal/perifoveal regions and unchanged in the periphery in the mutant macaque. Each data point represents one fluorescent image. (E) Immunostaining for EZRIN (pink) indicated the absence of RPE apical microvilli in the macular region of the mutant retina. (F) Immunostaining for MCT1 (green) showed decreased signals in the apical surface and processes of the RPE and photoreceptor outer segments in the mutant macaque macula. Statistical significance was determined by 2-way ANOVA and Šidák’s post hoc comparisons. (***P < 0.001).