June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Gene augmentation therapy improves inner and outer segment morphology and preserves retinal structure in a large animal model of CNGB1-retinitis pigmentosa
Author Affiliations & Notes
  • Laurence Mireille Occelli
    Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, United States
  • Paige A Winkler
    Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, United States
  • Vince A Chiodo
    University of Florida, Gainesville, Florida, United States
  • Sanford L Boye
    University of Florida, Gainesville, Florida, United States
  • William W Hauswirth
    University of Florida, Gainesville, Florida, United States
  • Simon M Petersen-Jones
    Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, United States
  • Footnotes
    Commercial Relationships   Laurence Occelli, None; Paige Winkler, None; Vince Chiodo, None; Sanford Boye, None; William Hauswirth, None; Simon Petersen-Jones, None
  • Footnotes
    Support  Myers-Dunlap Endowment for Canine Health (to SPJ), Michigan State University Endowed Research Funds (to SPJ).
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4508. doi:
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    • Get Citation

      Laurence Mireille Occelli, Paige A Winkler, Vince A Chiodo, Sanford L Boye, William W Hauswirth, Simon M Petersen-Jones; Gene augmentation therapy improves inner and outer segment morphology and preserves retinal structure in a large animal model of CNGB1-retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4508.

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

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Abstract

Purpose : Mutations in cyclic nucleotide gated channel beta 1 (CNGB1) cause autosomal recessive RP type 45 (RP45). Cngb1-/- dogs have marked loss of rod function and a slowly progressive photoreceptor degeneration recapitulating RP45. We showed at ARVO 2016 that gene augmentation therapy in Cngb1-/- dogs rescues rod function. Treated dogs had a dramatic restoration of rod electroretinogram (ERG) and improved vision in dim light. The purpose of this study was to investigate long-term effects of gene therapy in Cngb1-/- dogs.

Methods : Seven eyes of 5 Cngb1-/- dogs received a subretinal injection of 1x1012 vg of AAV2/5-hGRK1-cCngb1. Dark- and light-adapted electroretinograms (ERGs), vision testing, fundus imaging and structural preservation assessment by spectral-domain optical coherence tomography (SD-OCT) imaging was performed regularly post-injection. Immunohistochemistry (IHC) was performed on eyes collected 3, 6, 9 and 23 months post-injection.

Results : Gene augmentation rescued rod function (as measured by ERG and vision testing) up to 18 months post-injection (latest time point assessed). SD-OCT showed that there was improved definition of the zones representing the external limiting membrane to the interdigitation zone which was maintained over time. Following an initial decline in Receptor plus (REC+) thickness after subretinal injection further decline halted and thickness was preserved in the longer term (up to 23 months in two eyes). IHC confirmed photoreceptor preservation but only in the treated regions.

Conclusions : Rescue of rod function by gene augmentation therapy in Cngb1-/- dogs was maintained long term. There was also structural preservation with improved morphology of photoreceptor inner/outer segments. The initial continued decline in REC+ thickness following treatment may represent loss of rods prior to full expression of the transgene coupled with loss of any rods that had inadequate transgene expression or were already irreversibly committed to cell death. This study shows successful long-term gene therapy in a large animal model of RP45 making this an attractive disease for translational therapy.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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