Stanniocalcin-1 rescues photoreceptor degeneration in a porcine model of retinitis pigmentosa

Abstract

Purpose : Retinitis pigmentosa (RP) is a group of inherited diseases that cause blindness due to progressive degeneration of the photoreceptors. We previously reported that stanniocalcin-1 (STC-1) rescued photoreceptors in naturally occurring (Royal College of Surgeons) and rhodopsin transgenic (S334ter-3, S334ter-4, and P23H-1) rat models of RP. Herein, the potential therapeutic effect of STC-1 on RP in a large animal model, which resembles human ocular pathophysiology, was assessed in a recently developed Pro23His rhodopsin transgenic (TgP23H) pig.

Methods : TgP23H and wild type (WT) hybrid pig littermates were obtained from the National Swine Resource and Research Center. Recombinant human STC-1 (100 μL, 0.5 μg/μL) was injected intravitreally every 2 weeks from postnatal day 30 (P30) to P75. The contralateral eye was injected with balanced salt solution (BSS, 100 μL) as a control. Electroretinography (ERG) and spectral domain optical coherence tomography (SD-OCT) were performed to evaluate the retinal function and in vivo retinal morphology, respectively, at P90. Retinal tissue was collected at P45 for microarray analysis and at P90 for histologic and PCR analyses. For histologic analysis, photoreceptor nuclei and pyknotic nuclei were counted in epoxy resin embedded sections from corresponding retinal regions in the STC-1 and BSS treated eyes.

Results : Compared to the WT pig, the mean photopic a- and b-wave amplitudes at a stimulus intensity of 3.0 cd●s●m^-2 were decreased by 66.5% and 60.3%, respectively, in BSS treated TgP23H pig eyes. In contrast, the mean photopic a- and b-wave amplitudes were only reduced by 46.3% and 42.9% in STC-1 treated TgP23H pig eyes. The photoreceptor cell nuclear count was increased by 61.1% and the pyknotic nuclear count was decreased by 51.3% in STC-1 treated eyes compared to BSS treated eyes in the TgP23H pig. Microarray analysis revealed that 152 genes were upregulated >2-fold and 106 genes were downregulated >2-fold in STC-1 treated eyes. Recoverin and phosducin mRNA were upregulated by 3.1- and 2.1-fold, respectively, in STC-1 treated eyes compared to BSS treated eyes by quantitative RT-PCR. No apparent adverse effects were observed in STC-1 treated eyes by SD-OCT or histology.

Conclusions : STC-1 rescues photoreceptor degeneration, predominantly cones, in a porcine model of the most common form of autosomal dominant RP in the United States.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.