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.
Highlights
Retinitis pigmentosa (RP) is a collective term for a group of heterogeneous retinal degenerations that cause irreversible blindness and affect 1 in 3500 people worldwide.[1]
We showed that Tg Filial 1 (F1) progeny recapitulate functional and morphologic features similar to TgP23H miniswine founder 53-1, which exhibits an RP phenotype similar to the human form of the disease
Eyes from the 36 month-old Tg miniswine were fixed in 2.5% formaldehyde/2.5% glutaraldehyde mixture and because of this morphologic examination of the retina was limited to light and transmission electron microscopy
Summary
Retinitis pigmentosa (RP) is a collective term for a group of heterogeneous retinal degenerations that cause irreversible blindness and affect 1 in 3500 people worldwide.[1]. Their eyes do not have an area of retinal specialization populated extensively by cone photoreceptors. Swine have a cone-rich area of retinal specialization, the area centralis, which resembles the human macula.[7,8,9] Swine models of RP10–11 exhibit functional and morphologic characteristics[12,13,14] similar to the human phenotype. The only major drawback of swine models for general use in laboratory work and long-term projects is their large size. To circumvent this limitation, we developed Tg founder miniature swine that express the P23H RHO gene mutation.[11]
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