Long-term photoreceptor rescue in two rodent models of retinitis pigmentosa by adeno-associated virus delivery of Stanniocalcin-1

Abstract

Retinal degenerations, including age-related macular degeneration and the retinitis pigmentosa family of diseases, are among the leading causes of legal blindness in the United States. We previously found that Stanniocalcin-1 (STC-1) reduced photoreceptor loss in the S334ter-3 and Royal College of Surgeons rat models of retinal degeneration. The results were attributed in part to a reduction in oxidative stress. Herein, we tested the hypothesis that long-term delivery of STC-1 would provide therapeutic rescue in more chronic models of retinal degeneration. To achieve sustained delivery, we produced an adeno-associated virus construct (AAV) to express STC-1 (AAV-STC-1) under the control of a retinal ganglion cell targeting promoter human synapsin 1 (hSYN1). AAV-STC-1 was injected intravitreally into the P23H-1 and S334ter-4 rhodopsin transgenic rats at postnatal day 10. Tissues were collected at postnatal day 120 for confirmation of STC-1 overexpression and histologic and molecular analysis. Electroretinography (ERG) was performed in a cohort of animals at that time. Overexpression of STC-1 resulted in a significant preservation of photoreceptors as assessed by outer nuclear thickness in the P23H-1 (P<0.05) and the S334ter-4 (P<0.005) models compared to controls. Additionally, retinal function was significantly improved in the P23H-1 model with overexpressed STC-1 as assessed by ERG analysis (scotopic b-wave P<0.005 and photopic b-wave P<0.05). Microarray analysis identified common downstream gene expression changes that occurred in both models. Genes of interest based on their function were selected for validation by quantitative real time PCR and were significantly increased in the S334ter-4 model.

Intravitreal Stanniocalcin-1 Enhances New Blood Vessel Growth in a Rat Model of Laser-Induced Choroidal Neovascularization

“…On the contrary, functional (ERG) and histologic rescue by STC-1 were demonstrated. 24 , 25 Although it remains unclear whether these beneficial effects can be observed in the present study, the anti-apoptotic or pro-survival effect of STC-1 might have contributed to the growth of CNV as a reparative process after laser injury to the retinochoroidal tissue.…”

“…Administration of exogenous STC-1 enhances VEGF/VEGFR2 upregulation and promotes CNV formation after retinochoroidal laser injury. Because intravitreal STC-1 administration does not display neovascularization properties in inherited forms of retinal degeneration, 24 , 25 it remains unclear whether the promotion of CNV formation observed in the present study is specific to the physical injury (i.e., thermal laser photocoagulation) of the retina. Although STC-1 has been shown to protect photoreceptors from oxidative insult and enhance neural cell survival, the therapeutic potential of STC-1 in various forms of ocular disease deserves further investigation.…”

“… 52 We previously reported the protective role of STC-1 in reducing photoreceptor degeneration and oxidative stress in naturally occurring (Royal College of Surgeons) and rhodopsin transgenic (S334ter-3, S334ter-4, and P23H-1) rat models of inherited retinal degeneration. 24 , 25 In those studies, no retinal or choroidal neovascularization was observed, and no adverse ocular effects were reported after intravitreal STC-1 administration. On the contrary, functional (ERG) and histologic rescue by STC-1 were demonstrated.…”

“…We previously demonstrated that STC-1 can protect retinal morphology and function by reducing oxidative stress and photoreceptor apoptosis in four rodent models of inherited retinal degeneration. 24 , 25 Interestingly, the STC-1 gene was found to be highly upregulated in the vasculature of colon carcinomas. 26 Subsequently, its roles in modulating endothelial cell migration and morphogenesis were suggested in an in vitro cell culture study.…”

Use of Gene Therapy in Retinal Ganglion Cell Neuroprotection: Current Concepts and Future Directions

“…Although the exact mechanisms are unclear, STC-1 has been shown to be physiologically involved in the regulation of cellular calcium and phosphate homeostasis [ 61 ]. One group studied the effects of an AAV vector encoding STC-1 (AAV-STC-1) in two transgenic mice models of retinal degeneration (P23H-1 and S334ter-4) [ 25 ]. Both transgenic mice treated with AAV-STC-1 had significantly thicker optic nerve layers compared to untreated mice, but only P23H-1 treated mice had significantly improved scotopic and photopic B-waves when ERG responses were assessed.…”