May 2005
Volume 46, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2005
Replacement Gene Therapy Rescues Photoreceptor Degeneration in a Murine Model of Leber Congenital Amaurosis (LCA) Lacking RPGRIP
B.S. Pawlyk; A.J. Smith; P. Buch; M. Adamian; D.–H. Hong; M.A. Sandberg; R.R. Ali; T. Li
Author Affiliations & Notes
  • B.S. Pawlyk
    Berman–Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA
  • A.J. Smith
    Department of Molecular Therapy, Institute of Ophthalmology,University College London, London, United Kingdom
  • P. Buch
    Department of Molecular Therapy, Institute of Ophthalmology,University College London, London, United Kingdom
  • M. Adamian
    Berman–Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA
  • D.–H. Hong
    Berman–Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA
  • M.A. Sandberg
    Berman–Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA
  • R.R. Ali
    Department of Molecular Therapy, Institute of Ophthalmology,University College London, London, United Kingdom
  • T. Li
    Berman–Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA
  • Footnotes
    Commercial Relationships  B.S. Pawlyk, None; A.J. Smith, None; P. Buch, None; M. Adamian, None; D. Hong, None; M.A. Sandberg, None; R.R. Ali, None; T. Li, None.
  • Footnotes
    Support  NIH Grants EY10581and EY14188 and the Foundation Fighting Blindness
Investigative Ophthalmology & Visual Science May 2005, Vol.46, 5229. doi:
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      B.S. Pawlyk, A.J. Smith, P. Buch, M. Adamian, D.–H. Hong, M.A. Sandberg, R.R. Ali, T. Li; Replacement Gene Therapy Rescues Photoreceptor Degeneration in a Murine Model of Leber Congenital Amaurosis (LCA) Lacking RPGRIP . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5229.

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Abstract

Abstract: : Purpose: RPGRIP binds and anchors RPGR in the photoreceptor connecting cilia (CC) and is essential for photoreceptor function and survival. This study investigated whether somatic RPGRIP gene replacement rescues photoreceptor degeneration in mice lacking RPGRIP (RPGRIP–/–), a model of human LCA. Methods: A full–length RPGRIP cDNA was placed under the transcriptional control of a murine rhodopsin promoter and packaged into an AAV gene transfer vector (AAV–rho–RPGRIP). On postnatal day 18, RPGRIP–/– mice (n=16) were given a single subretinal injection of AAV–rho–RPGRIP (right eye; treatment) or normal saline (left eye; control) in the superior hemispheres. Electroretinograms (ERGs) were recorded from both eyes of each animal at 3, 4 and 5 months post–injection. Following the final ERG session at 5 months, mice were sacrificed and eyes were analyzed by immunostaining or by light and electron microscopy. Results:Treatment led to RPGRIP expression at the CC and restoration of normal RPGR localization to this subcellular compartment. At 5 months post–injection, treated eyes had significantly more photoreceptor cells (∼5 rows of outer nuclear layer) compared with control eyes (∼1.5 rows). Treated eyes developed well–organized and elongated photoreceptor inner and outer segments, while control eyes had severely shortened inner segments with little to no organized OS disc stacks at all. Analysis of ERG data between 3 and 5 months post–injection demonstrated significant preservation of photoreceptor function in the treated eyes. As expected, rescue was not pan–retinal but was more pronounced in the superior hemispheres coincident with the sites of subretinal injections and areas of the highest transgene (RPGRIP) expression. Conclusions: AAV–mediated RPGRIP gene therapy restores photoreceptor structure and function in a mouse model of LCA lacking RPGRIP. Given that mutant mice received treatment at an age when there was already a severe disruption of the photoreceptor cytoarchitecture, our results show that RPGRIP replacement gene therapy could prove effective in human retinas that have undergone significant degeneration.

Keywords: gene transfer/gene therapy • retinal degenerations: cell biology • retina 
© 2005, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.
Copyright © 2025 Association for Research in Vision and Ophthalmology.
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