Correlation of Physiology and Morphology in the P23H Rhodopsin Transgenic Swine Model of Retinitis Pigmentosa

Abstract

Purpose: : Despite the recent progress in retinal regeneration in rodents the efficacy of this therapeutic approach requires testing in a large animal model whose eye morphology and physiology is closer to humans. We recently developed a transgenic mini-swine model that carries the Pro23His (P23H) mutation in the rhodopsin gene, the most common form of autosomal dominant Retinitis Pigmentosa (RP) in human patients. We now present the long term follow up assessments of the transgenic mini-swine founders.

Methods: : Four male founders have been characterized over 21 months using both multifocal and full field electroretinograms (ERG). At their final assessment the eyes were enucleated, fixed and processed for morphological evaluation of the retinas. Light microscopy was used to examine and compare the retinal morphology to the final ERG assessments within each animal and across all four founders.

Results: : The transgenic mini-swine exhibits photoreceptor degeneration which mimics the phenotype found in humans with the P23H mutation. The transgene expression effect was evident in the electrophysiology showing an initial diminished rod response, followed by a subsequent diminished cone response; in the histology by a severe decrease in the photoreceptor density in the outer nuclear layer.

Conclusions: : The P23H transgenic mini-swine exhibits multiple photoreceptor dysfunction phenotypes which vary in onset, disease progression, and severity. There is close correlation between the electrophysiology and the retinal morphology of the founders of this novel animal model. These phenotypes are important tools to further understand the RP and develop new therapeutic strategies to replenish the photoreceptors and their normal function, ultimately restoring visual function.

Keywords: retinal degenerations: hereditary • electroretinography: non-clinical • photoreceptors