March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
AAV2/5 Mediated Gene Augmentation Rescues Photoreceptors in Canine Models of RPGR-XLRP
Author Affiliations & Notes
  • William A. Beltran
    Clinical Studies, Univ of Pennsylvania Sch Vet Med, Philadelphia, Pennsylvania
  • Artur V. Cideciyan
    Dept of Ophthalmology, Scheie Eye Institute, Philadelphia, Pennsylvania
  • Alfred S. Lewin
    Molecular Genetics & Microbio,
    University of Florida, Gainesville, Florida
  • Simone Iwabe
    Clinical Studies, Univ of Pennsylvania Sch Vet Med, Philadelphia, Pennsylvania
  • Hemant Khanna
    Ophthalmology, University of Massachusetts Medical School, Worcester, Massachusetts
  • Anand Swaroop
    N-NRL, Bldg 6, National Eye Institute, Bethesda, Maryland
  • William W. Hauswirth
    Ophthalmology,
    University of Florida, Gainesville, Florida
  • Samuel G. Jacobson
    Dept of Ophthalmology, Scheie Eye Institute, Philadelphia, Pennsylvania
  • Gustavo D. Aguirre
    Clinical Studies, Univ of Pennsylvania Sch Vet Med, Philadelphia, Pennsylvania
  • Footnotes
    Commercial Relationships  William A. Beltran, None; Artur V. Cideciyan, None; Alfred S. Lewin, None; Simone Iwabe, None; Hemant Khanna, None; Anand Swaroop, None; William W. Hauswirth, AGTC, Inc. (P); Samuel G. Jacobson, None; Gustavo D. Aguirre, None
  • Footnotes
    Support  EY-06855, -17549, -007961, -021721, Foundation Fighting Blindness, Fight for Sight Nowak family grant, Macular Vision Research Foundation, Van Sloun Fund , Research to Prevent Blindness, Inc.
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 1919. doi:
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      William A. Beltran, Artur V. Cideciyan, Alfred S. Lewin, Simone Iwabe, Hemant Khanna, Anand Swaroop, William W. Hauswirth, Samuel G. Jacobson, Gustavo D. Aguirre; AAV2/5 Mediated Gene Augmentation Rescues Photoreceptors in Canine Models of RPGR-XLRP. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1919.

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

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Abstract

Purpose: : Mutations in the RPGR gene are the most common cause of X-linked RP in man. Two naturally-occurring canine models (XLPRA1 and XLPRA2) with distinct deletions in RPGRORF15 recapitulate the spectrum of disease phenotypes found in humans. Both models were used to test if AAV-mediated gene transfer of human RPGRORF15 cDNA can rescue photoreceptors when delivered prior to (XLPRA1) or after (XLPRA2) the onset of degeneration.

Methods: : Two AAV2/5 vector constructs (titer: 1.51 x E11 vg/ml) carrying full-length human RPGRORF15 cDNA under the control of either a hGRK1 or hIRBP promoter were injected subretinally in XLPRA1 (150 ul at 28 weeks), and XLPRA2 (70 ul at 5 weeks) dogs. Contra-lateral eyes were sham-injected with BSS and served as controls. Photoreceptor structure and function was assessed by means of non-invasive retinal imaging (cSLO/ SD-OCT) and ERG, and by morphology/IHC at termination.

Results: : In vivo retinal imaging showed preserved ONL thickness and IS/OS structure in the treated retinal areas. Rod and cone function was greater in treated than in control retinas. Morphology studies confirmed the rescue of photoreceptor structure within the treated areas, as well as the reversal of rod and M/L cone opsin mislocalization and the prevention of rod neurite sprouting. Potent expression of the hRPGR transgene was found exclusively in photoreceptors located within the treated areas.

Conclusions: : These results show for the first time that gene transfer of the full length human RPGRORF15 cDNA provides both structural and functional rescue in an animal model of RPGR-XLRP.

Keywords: gene transfer/gene therapy • retina • photoreceptors 
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