May 2003
Volume 44, Issue 13
ARVO Annual Meeting Abstract  |   May 2003
The Lessons of rAAV Mediated RPE65 Gene Delivery from Mouse and Dog Models of LCA
Author Affiliations & Notes
  • E.P. Rakoczy
    Ctr for Ophthal & Vision Sci, Univ of Western Australia, Perth, Australia
  • C.M. Lai
    Ctr for Ophthal & Vision Sci, Univ of Western Australia, Perth, Australia
  • M. Brankov
    Molecular Ophthalmology, Lions Eye Institute, Perth, Australia
  • M.T. Redmond
    Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, Maryland, MD, United States
  • X. Zhou
    Virus Vector Core Facility, Gene Therapy Centre, University of North Carolina, North Carolina, NC, United States
  • K. Narfstrom
    Veterinary Medicine and Surgery, University of Missouri-Columbia, Missouri, MO, United States
  • Footnotes
    Commercial Relationships  E.P. Rakoczy, None; C.M. Lai, None; M. Brankov, None; M.T. Redmond, None; X. Zhou, None; K. Narfstrom, None.
  • Footnotes
    Support  Foundation for Fighting Blindess (USA), NHMRC (Australia)
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 3593. doi:
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      E.P. Rakoczy, C.M. Lai, M. Brankov, M.T. Redmond, X. Zhou, K. Narfstrom; The Lessons of rAAV Mediated RPE65 Gene Delivery from Mouse and Dog Models of LCA . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3593.

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

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Abstract: : Purpose: To compare the response to recombinant adenoassociated virus (rAAV) mediated RPE65 gene expression in the Rpe65-/- mouse and Briard dog models of Leber’s Congenital Amarousis (LCA). Methods: Animals were subretinally injected with rAAV.RPE65 and at different time points subjected to behavioral studies,and electroretinography (ERG) recordings. Following euthanasia the enucleated eyes were analyzed by histology, immunohistochemistry and electronmicroscopy. Results: Following subretinal injection, rAAV.GFP and rAAV.RPE65 transgene expression was readily detectable by fluorescent microscopy and immunohistochemistry, respectively in both models and was maintained up to 18 months as shown in the mouse. ERGs showed that dark-adapted b-wave amplitudes recovered to an average of 25% of normal, and light adapted b-wave amplitudes to 20% of normal amplitudes in the mouse model and slightly more in the dog model and were not reduced in dogs during a 9-12 months follow-up period. No systemic side effects were observed in either model but 75% of rAAV.RPE65-injected dogs developed uveitis. Ultrastructurally a reversal of RPE lipid droplet accumulation at the rAAV.RPE65 injection site was observed in both animals models. In the mouse model there was a recovery of up to 50% of short wavelength cone opsin-positive cells. However, this functional recovery was not accompanied by a reduction of the degenerative process of photoreceptors in affected mice. Conclusions: These observations have significant clinical implications as they suggest that gene therapy might provide a treatment that can prevent blindness or delay the onset of blindness in LCA sufferers, potentially for decades.

Keywords: animal model • gene transfer/gene therapy • retinal degenerations: hereditary 

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