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 2

The Q327-mutant macaque exhibited clinical manifestations of Stage 1 Best vitelliform macular dystrophy.

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The Q327-mutant macaque exhibited clinical manifestations of Stage 1 Bes...
(A) SD-OCT scans of the mutant macaque and an age-matched control over 26 months of follow up. The mutant animal exhibited a progressively enlarging subfoveal cleft (area outlined in yellow) in both eyes. Deposits in the subfoveal cleft were also observed (white arrows). The first month SD-OCT image in A is the same as the mutant SD-OCT image shown in Figure 1A. (B) The subfoveal cleft areas from both eyes of the mutant macaque were enlarged during the 26 months of follow up. (C) Total retinal thickness of the mutant macaque decreased over time in both eyes, while that of the control remained unaltered. (D) The thickness of the parapapillary retinal nerve fiber layer remained unchanged in both the mutant and age-matched control macaque. (E) Blue light fundus autofluorescence (B-AF) examinations disclosed a slight increase in the size of the autofluorescence lesion in the right eye over 19 months from the seventh-month follow-up visit to the 26th-month follow-up visit. The autofluorescence lesion in the left eye was not as prominent.The red box indicates the enlarged area in the adjacent image. (F) Representative ERG waveforms of mutant animal and control, including scotopic 0.01, photopic 10.0, and the photopic negative response (PhNR). ONL, outer nuclear layer; B-AF, blue light fundus autofluorescence; ERG, electrophysiology.