Progression of Pro23His Retinopathy in a Miniature Swine Model of Retinitis Pigmentosa

Abstract

PurposeWe characterize the progression of retinopathy in Filial 1 (F1) progeny of a transgenic (Tg) founder miniswine exhibiting severe Pro23His (P23H) retinopathy.MethodsThe F1 TgP23H miniswine progeny were created by crossing TgP23H founder miniswine 53-1 with wild type (WT) inbred miniature swine. Scotopic (rod-driven) and photopic (cone-driven) retinal functions were evaluated in F1 TgP23H and WT littermates using full field electroretinograms (ffERGs) at 1, 2, 3, 6, 9, 12, and 18 months of age, as well as the Tg founder miniswine at 6 years of age. Miniswine were euthanized and their retinas processed for morphologic evaluation at the light and electron microscopic level. Retinal morphology of a 36-month-old Tg miniswine also was examined.ResultsWild type littermates reached mature scotopic and photopic retinal function by 3 months, while TgP23H miniswine showed abnormal scotopic ffERGs at the earliest time point, 1 month, and depressed photopic ffERGs after 2 months. Rod and cone photoreceptors (PR) exhibited morphologic abnormalities and dropout from the outer nuclear layer at 1 month, with only a monolayer of cone PR somata remaining after 2 months. The retinas showed progressive neural remodeling of the outer retina that included dendritic retraction of rod bipolar cells and glial seal formation by Müller cells. The TgP23H founder miniswine showed cone PR with relatively intact morphology exclusive to the area centralis.ConclusionsThe F1 Tg miniswine and the TgP23H founder miniswine exhibit similar retinopathy.Translational RelevanceTgP23H miniswine are a useful large-eye model to study pathogenesis and preservation cone PRs in humans with retinitis pigmentosa.

Noninvasive Imaging and Correlative Histology of Cone Photoreceptor Structure in the Pig Retina

“…5). Consistent with our published observations that only a single layer of cones remains,53 the OCT B-scan from a P180 TgP23H pig showed a similar outer retinal band structure between the optic nerve and midperipheral retina (left and right, respectively; Fig. 6A).…”

“…Previous studies have characterized retinal morphology and function in the TgP23H pig model using histology and ERG (Piri N., et al, IOVS . 2018;59:ARVO E-abstract 729)39,53,60 and shown that cone inner segments are maintained until ∼1 year of age, although they appear dysmorphic, for example, swollen 39. This change is reflected in our AOSLO images, which show residual inner segments at P180, and our split detector images, which show a heterogeneity among TgP23H cone inner segments, with some showing exaggerated shadowing.…”

Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

“…Specific ablation of rod photoreceptors in transgenic mice results in the failure of cone cells in elaborating their outer segments [82,83]. It was observed in various animal models of RP including rodents, pigs, dogs, and even toads [83][84][85][86]. The analysis of the kinetics of rod and cone cells death in several mouse models of RP excludes that dying rods are toxically damaging the cones [87].…”

1H NMR Spectroscopy Characterization of Porcine Vitreous Humor in Physiological and Photoreceptor Degeneration Conditions

“…21 The importance of animal models of retinal degeneration and their value in the biomedical field has been widely recognized in recent years and has led to the development of different models. 22 To date, several porcine models of photoreceptor degeneration have been proposed, 23,24 including the transgenic miniature swine, for example, the TgP23H model of retinitis pigmentosa, 24 or induced by an intravenous injection of iodoacetic acid (IAA). 21,25,26 The latter chemical compound causes an inhibition of anaerobic glycolysis through the reaction with the glyceraldehyde-3-phosphate dehydrogenase.…”