May 2005
Volume 46, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2005
Subretinal CNTF Gene Delivery in a Feline Model: Cell Transfection and Morphological Sequelae
Author Affiliations & Notes
  • C.S. Sethi
    Pathology,
    Institute of Ophthalmology, London, United Kingdom
  • F. Schlichtenbrede
    Molecular Genetics,
    Institute of Ophthalmology, London, United Kingdom
  • G.P. Lewis
    Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA
  • S.K. Fisher
    Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA
  • P.J. Luthert
    Pathology,
    Institute of Ophthalmology, London, United Kingdom
  • D.G. Charteris
    Vitreo–Retinal Research Unit, Moorfields Eye Hospital, London, United Kingdom
  • R.R. Ali
    Molecular Genetics,
    Institute of Ophthalmology, London, United Kingdom
  • Footnotes
    Commercial Relationships  C.S. Sethi, None; F. Schlichtenbrede, None; G.P. Lewis, None; S.K. Fisher, None; P.J. Luthert, None; D.G. Charteris, None; R.R. Ali, None.
  • Footnotes
    Support  Medical Research Council (UK) Grant G84/5452; NIH Grant EY–00888; Sir Jules Thorn Charitable Trust
Investigative Ophthalmology & Visual Science May 2005, Vol.46, 5217. doi:
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      C.S. Sethi, F. Schlichtenbrede, G.P. Lewis, S.K. Fisher, P.J. Luthert, D.G. Charteris, R.R. Ali; Subretinal CNTF Gene Delivery in a Feline Model: Cell Transfection and Morphological Sequelae . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5217.

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

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Abstract

Abstract: : Purpose:Ciliary Neurotrophic Factor (CNTF) gene expression can ameliorate photoreceptor loss in retinal degeneration models. However, recent evidence suggests that this may adversely affect ERG amplitudes in wild–type animals. We have assessed subretinal CNTF gene delivery in feline retina, using a recombinant adeno–associated virus vector (rAAV) with CMV promoter and fluorescent tag (GFP). Methods: Subretinal cannulae delivered constructs to the subretinal space of control (n=2: rAAV.CMV.GFP) and test (n=4: rAAV.CMV.CNTF.GFP) animals, which were monitored clinically and by fluorescence fundoscopy. After 8 weeks, tissue was processed for confocal microscopy, with a variety of probes. Results: Transfection was achieved in rods, some cones and occasional Müller cells. All treatment blebs flattened, but test animals transfected with the CNTF gene subsequently developed tractional retinal detachments with epiretinal membrane formation. Neurite extension was observed from rods, bipolar cells and horizontal cells, with accumulation of neurofilament in ganglion cells and a marked microglial response. Control retinas remained flat with normal histology. Conclusions: Our results demonstrate the feasibility of an rAAV vector–mediated approach for the treatment of retinal disease by gene delivery, in a well–characterised animal model. There are, however, concerns in using a CNTF–based strategy given our observation of its effect on retinal cell biology.

Keywords: gene transfer/gene therapy • neuroprotection • retinal degenerations: cell biology 
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