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 5

The Q327 mutant macaque exhibits mitochondrial-negative and -positive lipid deposits in the macula.

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The Q327 mutant macaque exhibits mitochondrial-negative and -positive li...
(A–C) Representative images from immunostaining of BODIPY (green), TOM20 (red), and DAPI (blue) in different retinal regions, including fovea, parafovea/perifovea, and periphery. The bottom row shows zoomed-in views of the areas indicated by boxes in the top row. (A and B) In the fovea (A) and parafovea/perifovea (B), there was the accumulation of 2 types of BODIPY high deposits: deposits beneath the outer segments were TOM20 negative (indicated by yellow circles), while deposits above the outer segments were TOM20 positive (indicated by the white arrowheads). Mitochondria in the inner-segment region of photoreceptors, with low BODIPY signal, are outlined in white. A wavy distribution pattern of mitochondria was observed in the mutant animal. (C) The peripheral retina of the mutant animal showed a normally organized ellipsoid zone band with mitochondria, and deposits were rarely detected. TOM20, Translocase of outer mitochondrial membrane 20; EZ, ellipsoid zone; OS, outer segments; IS, inner segments.