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 3

Change in outer nuclear layer and RPE thickness over time in the Q327-mutant macaque.

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Change in outer nuclear layer and RPE thickness over time in the Q327-mu...
(A) Schematic diagram showing the four directions and anatomical subdivisions of the retina (left panel) and associated segmentation (right panel) for analysis. The retina was divided into nasal (N), inferior (I), temporal (T), and superior (S), relative to the fovea (no. 1), parafoveal region (no. 2), and perifoveal region (no. 3). The OCT boundaries used to measure total retinal thickness, thickness of the ONL, and thickness of the RPE-IZ region, respectively, are denoted (right panel). In this study, the fovea was defined as a 1.0 mm diameter ring centered on the foveola, the parafovea was defined as an annulus centered on the fovea between circles with diameters of 1.0 mm and 2.22 mm, and the perifovea was defined as an annulus centered on the fovea between the circles with diameters of 2.22 mm and 3.45 mm. The position of the foveola was determined by manually determining the central fovea on the horizontal scans. (B and C) The baseline thickness of RPE-IZ (B) and ONL (C) in the first OCT examination from the mutant macaque and the age-matched control macaque. (D–G) The thickness change of RPE-IZ and ONL during the follow-up visits compared to the initial examination are displayed. RPE-IZ, the RPE-Bruch’s membrane (BM) complex and the RPE-photoreceptor interdigitation zone; ONL, the outer nuclear layer.