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P. J. DeMarco, R. Prather, J. W. Ross, E. M. Walters, M. A. McCall, H. J. Kaplan; Functional Assessment of a Pro23His (P23H) Transgenic Mini-Swine Model of Retinitis Pigmentosa (RP). Invest. Ophthalmol. Vis. Sci. 2010;51(13):5569.
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An easily propagated transgenic large animal model with retinal morphology similar to humans would be an important breakthrough in the discovery of therapeutic interventions for RP. We have developed and characterized a transgenic mini-swine model of RP that carries the mutant P23H human rhodopsin gene, which underlies a common form of RP in the human population.
Six male mini-swine (NIH SLAcc haplotype) carrying a mutant human P23H rhodopsin transgene were produced using somatic cell nuclear transfer. Dark- and-light adapted ERGs were recorded at 3 month intervals for 1 year using a standard ISCEV protocol to track disease onset and progression. Clinical fundus examinations also were performed. PCR-based genotyping tracked transgene inheritance in the offspring (F1s) resulting from artificial insemination (AI) of a domestic swine from one founder. Photoreceptor apoptosis was determined histologically in these F1s using tunnel.
Compared to controls, the ERGs of all founder transgenic mini-swine showed reductions consistent with photoreceptor degeneration induced by transgene expression. Across founders, onset and disease progression of the ERG phenotype varied. Some showed effects on the rod ERG as early as three months, others showed variation in the onset changes in both rod and cone ERGs. By 6 months all founders had abnormal rod and cone ERGs, although severity varied. Fifty percent of the F1s resulting from AI inherited the transgene and exhibited more photoreceptor apoptosis at postnatal day 1 than littermates without the transgene.
The P23H transgenic mini-swine exhibits rod and cone dysfunction consistent with the P23H phenotype in RP patients. The diversity of the ERG phenotype across founders may result from transgene insertion site. Mendelian transmission to F1s indicates a single insertion site and photoreceptor degeneration is correlated with transgene inheritance. Thus these transgenic miniswine, which are small in size and propagated via AI, are an excellent large animal model of human RP. They will be useful for developing therapeutic approaches to delay or restore vision loss due to photoreceptor degeneration.
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