April 2011
Volume 52, Issue 14
ARVO Annual Meeting Abstract  |   April 2011
AAV-mediated Delivery of Rod-derived Cone Viability Factor in a Mouse Model of Retinal Degeneration
Author Affiliations & Notes
  • Leah C. Byrne
    Neuroscience, UC Berkeley, Berkeley, California
  • Emmanuelle Clérin
    Genetics, Institut de la Vision, UPMC, Paris, France
  • Irene Lee-Rivera
    Genetics, Institut de la Vision, UPMC, Paris, France
  • Gabriel Luna
    Neuroscience Research Institute, University of California, Santa Barbara, Berkeley, California
  • Steven K. Fisher
    Neuroscience Research Institute, University of California, Santa Barbara, Berkeley, California
  • Jean Bennett
    310 Stellar-Chance Labs, University of Pennsylvania, Philadelphia, Pennsylvania
  • Jose A. Sahel
    UMR-S 968, Institut de la Vision, Paris, France
  • John G. Flannery
    Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California
  • Thierry D. Leveillard
    Genetique, Institut De La Vision, Paris, France
  • Footnotes
    Commercial Relationships  Leah C. Byrne, None; Emmanuelle Clérin, None; Irene Lee-Rivera, None; Gabriel Luna, None; Steven K. Fisher, None; Jean Bennett, None; Jose A. Sahel, Patent-holder on the use of RdCVF (P); John G. Flannery, None; Thierry D. Leveillard, patent-holder on the use of RdCVF (P)
  • Footnotes
    Support  Bourse Chateaubriand, NIH Grant EY016994, and the Foundation for Fighting Blindness
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 1395. doi:
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      Leah C. Byrne, Emmanuelle Clérin, Irene Lee-Rivera, Gabriel Luna, Steven K. Fisher, Jean Bennett, Jose A. Sahel, John G. Flannery, Thierry D. Leveillard; AAV-mediated Delivery of Rod-derived Cone Viability Factor in a Mouse Model of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1395.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : The bifunctional gene Nxnl1 encodes two products through alternative splicing. Rod-derived cone viability factor (RdCVF), a truncated thioredoxin-like protein, is secreted and has been shown to have a protective effect on the survival of cones in rodent models of retinitis pigmentosa (RP), while the full length protein, RdCVFL, contains a thioredoxin fold and may be involved in oxidative signaling. The aim of these experiments is to further investigate the bifunctional nature of the Nxnl1 gene products, and to evaluate the effects of AAV-mediated delivery of RdCVF and RdCVFL in the rd10 mouse model of retinal degeneration and the S334ter rat, a model of dominant RP.

Methods: : AAV vectors were used to deliver cDNA encoding RdCVF or RdCVFL one day after birth via tail vein injections in mice or via intravitreal injections at p14 in rd10 mice or S334ter-3 rats. The viral vectors were self-complementary ShH10Y445F, a variant of AAV6 that selectively infects Müller glia from the vitreous, or AAV92Yf (carrying 2 tyrosine mutations) injected at P1 into the tail vein of mice. A CAG promoter drove transgene expression. Electroretinograms were recorded to evaluate rescue of rod and cone-mediated responses. The density of cones was evaluated to determine the effect of expression on cone survival, and cone morphology was studied. ONL measurements were taken as a measure of rod survival.

Results: : Injection of ShH10Y445F and AAV92YF leads to efficient expression of GFP, RdCVF and RdCVFL. Delivery of RdCVF via tail vein injections or intravitreal injections leads to functional rescue of the cone-mediated photopic ERG.

Conclusions: : These results support the role of RdCVF as a secreted factor capable of promoting cone survival, as well as the bifunctional nature of the nxnl1 gene. The AAV variant ShH10 efficiently infects Müller glia via intravitreal injection. Targeted Müller cells are capable of delivering RdCVF to its targets in the retina. Additionally, AAV9 infects retinal cells after tail vein injection, and leads to high levels of transgene expression.

Keywords: gene transfer/gene therapy • Muller cells • retinal degenerations: hereditary 

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