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

• Published in: Experimental eye research Vol. 165; pp. 175 - 181
• Main Authors: Roddy, Gavin W., Yasumura, Douglas, Matthes, Michael T., Alavi, Marcel V., Boye, Sanford L., Rosa, Robert H., Fautsch, Michael P., Hauswirth, William W., LaVail, Matthew M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-12-2017
• Subjects: Animals; Dependovirus; Disease Models, Animal; Electroretinography; Glycoproteins - administration & dosage; Glycoproteins - therapeutic use; Neuroprotection; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - therapeutic use; P23H; Photoreceptor Cells, Vertebrate - pathology; Rats; Rats, Transgenic; Retinal degeneration; Retinitis Pigmentosa - drug therapy; Retinitis Pigmentosa - pathology; Rhodopsin; S334ter; Stanniocalcin-1; Retinal degeneration; Neuroprotection; P23H; Rhodopsin; Stanniocalcin-1; S334ter
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2017.09.011

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 (AAV) construct 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.