May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Gene Replacement Therapy in a Mouse Model of AIPL1-Related LCA Results in Restoration of Beta-PDE Transport and Preservation of Photoreceptor Cells
Author Affiliations & Notes
  • M. Tan
    Division of Molecular Therapy, Institute of Ophthalmology, University College London, United Kingdom
  • A. J. Smith
    Division of Molecular Therapy, Institute of Ophthalmology, University College London, United Kingdom
  • J. W. Bainbridge
    Division of Molecular Therapy, UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom
    NIHR Faculty, UCL/MEH London, United Kingdom
  • B. S. Pawlyk
    Berman-Gund Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Massachusetts
  • T. Li
    Berman-Gund Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Massachusetts
  • R. R. Ali
    Division of Molecular Therapy, Institute of Ophthalmology, University College London, United Kingdom
    NIHR Faculty, UCL/MEH London, United Kingdom
  • Footnotes
    Commercial Relationships  M. Tan, None; A.J. Smith, None; J.W. Bainbridge, None; B.S. Pawlyk, None; T. Li, None; R.R. Ali, None.
  • Footnotes
    Support  Medical Research Council UK, Wellcome Trust UK, Fighting Blindness, Ireland, EU NoE -CliniGene
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 1130. doi:https://doi.org/
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      M. Tan, A. J. Smith, J. W. Bainbridge, B. S. Pawlyk, T. Li, R. R. Ali; Gene Replacement Therapy in a Mouse Model of AIPL1-Related LCA Results in Restoration of Beta-PDE Transport and Preservation of Photoreceptor Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1130. doi: https://doi.org/.

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

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Abstract

Purpose: : Defects in the gene encoding aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) result in Lebers Congenital Amaurosis (LCA) which is a severe form of early onset retinal dystrophy. The gene is expressed in rods and cones and encodes a specialised chaperone for the biosynthesis of cGMP phosphodiesterase (PDE), an enzyme involved in phototransduction. The aim of this study was to investigate the efficacy of gene replacement therapy in a hypomorphic AIPL1 transgenic mouse model.

Methods: : An AIPL1 expression cassette, driven by a CMV promoter, was packaged into a recombinant adeno-associated virus (rAAV) - serotype 2. The rAAV vector was delivered into the right eyes of AIPL1 knockdown transgenic mice by two subretinal injections into the superior and inferior hemispheres. The contralateral eyes were uninjected to serve as an internal control. Full field electroretinograms (ERGs) were recorded from both eyes simultaneously at monthly intervals up to 7 months. The retinas were analysed by immunostaining and histology after final follow-up.

Results: : . ERG b-wave amplitudes recorded from the treated eyes were 23% higher than untreated eyes (p<0.05) at 5 months after injection and this difference was maintained up to 7 months demonstrating sustained preservation of function. Treated eyes had thicker outer nuclear cell layer and better preservation of retinal architecture. Morphometric analysis showed that treated eyes had 30% more photoreceptor cells (p<0.003). Immunohistochemistry showed increased AIPL1 expression and correct localization of cGMP PDE to the outer segments in treated eyes, while in untreated eyes, cGMP PDE was mislocalised to inner segments.

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