June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Corrective Gene Therapy for RPGR-XLRP Rescues a Canine Model at Mid-Stage Disease
Author Affiliations & Notes
  • William Beltran
    Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA
  • Artur Cideciyan
    Ophthalmology, Scheie Eye Institute, School of Medicine, University of Pennsylvania, Philadelphia, PA
  • Alfred Lewin
    Molecular Genetics & Microbiology, University of Florida, Gainesville, FL
  • Simone Iwabe
    Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA
  • Sanford Boye
    Ophthalmology, University of Florida, Gainesville, FL
  • William Hauswirth
    Ophthalmology, University of Florida, Gainesville, FL
  • Samuel Jacobson
    Ophthalmology, Scheie Eye Institute, School of Medicine, University of Pennsylvania, Philadelphia, PA
  • Gustavo Aguirre
    Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 2707. doi:
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      William Beltran, Artur Cideciyan, Alfred Lewin, Simone Iwabe, Sanford Boye, William Hauswirth, Samuel Jacobson, Gustavo Aguirre; Corrective Gene Therapy for RPGR-XLRP Rescues a Canine Model at Mid-Stage Disease. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2707.

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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, a condition that is currently still incurable. However, we have recently shown in two canine models that AAV-mediated gene transfer of human RPGRORF15 cDNA can rescue photoreceptors when delivered prior to the onset, or at an early stage of degeneration. We now investigate whether gene therapy delivered at a more advanced stage of disease can still provide a positive outcome.

Methods: An AAV2/5 vector construct (titer: 1.51 x 1011 vg/ml) carrying full-length human RPGRORF15 cDNA under the control of a hIRBP promoter was injected subretinally in three 12-wk-old XLPRA2 dogs. At that age, there is on-going cell death and the ONL thickness is reduced by ~ 40%. In addition, one XLPRA2 dog was injected shortly after the onset of disease (5.1 wks of age) as an early disease stage control. Contra-lateral eyes were either injected with BSS, or received a similar dose of viral construct intravitreally. Photoreceptor structure and function was assessed by means of non-invasive retinal imaging (cSLO/ SD-OCT) and ERG at 39 and 42 weeks of age, respectively.

Results: In vivo retinal imaging showed preserved ONL thickness in the treated retinal areas. ERG function was greater in treated than in control eyes, with more than an 8-, 1.2-, and 1.6-fold difference in the amplitudes of rod, mixed rod-cone, and cone 29 Hz flicker responses, respectively. ONL thickness was better preserved in the animal treated at 5.1 weeks than in the 3 dogs injected at 12 weeks of age, and ERG amplitudes were in average 1.6-fold higher.

Conclusions: These results expand our recently published findings by showing that a sustained and beneficial effect on photoreceptor structure and retinal function can be achieved even when delivering RPGR gene augmentation at a mid-stage of XLRP disease. This has important translational application given that most patients are likely to have relatively advanced disease at the time of treatment.

Keywords: 538 gene transfer/gene therapy • 696 retinal degenerations: hereditary • 648 photoreceptors  
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