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

Gavin W. Roddy, Douglas Yasumura, Michael T. Matthes, Marcel V. Alavi, Sanford L. Boye, Robert H. Rosa, Michael P Fautsch, William W. Hauswirth, Matthew M. LaVail

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 (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.

Original languageEnglish (US)
Pages (from-to)175-181
Number of pages7
JournalExperimental Eye Research
Volume165
DOIs
StatePublished - Dec 1 2017

Fingerprint

Dependovirus
Retinitis Pigmentosa
Rodentia
Retinal Degeneration
Electroretinography
Synapsins
Transgenic Rats
Rhodopsin
Retinal Ganglion Cells
Macular Degeneration
Blindness
Microarray Analysis
teleocalcin
Real-Time Polymerase Chain Reaction
Oxidative Stress
Gene Expression
Genes

Keywords

  • Neuroprotection
  • P23H
  • Retinal degeneration
  • Rhodopsin
  • S334ter
  • Stanniocalcin-1

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

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

In: Experimental Eye Research, Vol. 165, 01.12.2017, p. 175-181.

Research output: Contribution to journalArticle

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. / Long-term photoreceptor rescue in two rodent models of retinitis pigmentosa by adeno-associated virus delivery of Stanniocalcin-1. In: Experimental Eye Research. 2017 ; Vol. 165. pp. 175-181.
@article{e242ea9597c347b996f0015c471b4c98,
title = "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 (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.",
keywords = "Neuroprotection, P23H, Retinal degeneration, Rhodopsin, S334ter, Stanniocalcin-1",
author = "Roddy, {Gavin W.} and Douglas Yasumura and Matthes, {Michael T.} and Alavi, {Marcel V.} and Boye, {Sanford L.} and Rosa, {Robert H.} and Fautsch, {Michael P} and Hauswirth, {William W.} and LaVail, {Matthew M.}",
year = "2017",
month = "12",
day = "1",
doi = "10.1016/j.exer.2017.09.011",
language = "English (US)",
volume = "165",
pages = "175--181",
journal = "Experimental Eye Research",
issn = "0014-4835",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Long-term photoreceptor rescue in two rodent models of retinitis pigmentosa by adeno-associated virus delivery of Stanniocalcin-1

AU - Roddy, Gavin W.

AU - Yasumura, Douglas

AU - Matthes, Michael T.

AU - Alavi, Marcel V.

AU - Boye, Sanford L.

AU - Rosa, Robert H.

AU - Fautsch, Michael P

AU - Hauswirth, William W.

AU - LaVail, Matthew M.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - Neuroprotection

KW - P23H

KW - Retinal degeneration

KW - Rhodopsin

KW - S334ter

KW - Stanniocalcin-1

UR - http://www.scopus.com/inward/record.url?scp=85032012431&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032012431&partnerID=8YFLogxK

U2 - 10.1016/j.exer.2017.09.011

DO - 10.1016/j.exer.2017.09.011

M3 - Article

VL - 165

SP - 175

EP - 181

JO - Experimental Eye Research

JF - Experimental Eye Research

SN - 0014-4835

ER -