March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
AAV-mediated Gene Therapy Restores Retinal Function And Vision In The PDE6β-deficient Dog
Author Affiliations & Notes
  • Lolita Monnier
    Institut de Recherche Therapeutique 1, Laboratoire de Therapie Genique INSERM UMR 649, Nantes, France
  • Elsa Lhériteau
    Institut de Recherche Therapeutique 1, Laboratoire de Therapie Genique INSERM UMR 649, Nantes, France
  • Michel Weber
    Service d'Ophtalmologie, CHU-Hôtel Dieu, Nantes, France
  • Guylène Le Meur
    Service d'Ophtalmologie, CHU-Hôtel Dieu, Nantes, France
  • Jack-Yves Deschamps
    ONIRIS, Nantes-Atlantic College of Veterinary Medicine, Food Science and Engineering, Emergency and Critical Care Unit, Nantes, France
  • Nathalie Provost
    Institut de Recherche Therapeutique 1, Laboratoire de Therapie Genique INSERM UMR 649, Nantes, France
  • Lyse Libeau
    Institut de Recherche Therapeutique 1, Laboratoire de Therapie Genique INSERM UMR 649, Nantes, France
    Service d'Ophtalmologie, CHU-Hôtel Dieu, Nantes, France
  • Caroline Guihal
    Institut de Recherche Therapeutique 1, Laboratoire de Therapie Genique INSERM UMR 649, Nantes, France
  • Philippe Moullier
    Institut de Recherche Therapeutique 1, Laboratoire de Therapie Genique INSERM UMR 649, Nantes, France
    Department of Molecular Genetics and Microbiology, University of Florida, College of Medicine, Gainesville, Florida
  • Fabienne Rolling
    Institut de Recherche Therapeutique 1, Laboratoire de Therapie Genique INSERM UMR 649, Nantes, France
  • Footnotes
    Commercial Relationships  Lolita Monnier, None; Elsa Lhériteau, None; Michel Weber, None; Guylène Le Meur, None; Jack-Yves Deschamps, None; Nathalie Provost, None; Lyse Libeau, None; Caroline Guihal, None; Philippe Moullier, None; Fabienne Rolling, None
  • Footnotes
    Support  Association Française contre les Myopathies (AFM), Ministère de l'Enseignement Supérieur et de la Recherche
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 1901. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Lolita Monnier, Elsa Lhériteau, Michel Weber, Guylène Le Meur, Jack-Yves Deschamps, Nathalie Provost, Lyse Libeau, Caroline Guihal, Philippe Moullier, Fabienne Rolling; AAV-mediated Gene Therapy Restores Retinal Function And Vision In The PDE6β-deficient Dog. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1901.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: : Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. Previous studies have tested gene replacement therapy in the rd10 mouse model of PDE6β-RP using adeno-associated virus (AAV) serotype 5 or 8 vectors expressing murine pde6β. They documented restoration of rod function and preservation of retinal morphology. The aim of our preclinical study was to test AAV-mediated gene replacement therapy in the rod-cone dysplasia type 1 (rcd1) dog, a naturally occurring large animal model of PDE6β deficiency that strongly replicates the human pathology.

Methods: : We generated AAV2/5 and AAV2/8 vectors expressing canine pde6β cDNA under the control of the photoreceptor-specific rhodopsin kinase promoter. One hundred microliter of each vector was subretinally injected to one eye of four rcd1 dogs. The contralateral eye remained uninjected. Retinal morphology was assessed by fundus imaging, optical coherence tomography, histology and immunohistochemistry. Retinal function was tested on all treated dogs using bilateral electroretinography (ERG) at 1, 3, 6, 9 and 12 months after treatment. Moreover, vision was evaluated in all animals using behavioral testing under dim light conditions.

Results: : In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5hRK.cpde6β- and AAV2/8hRK.cpde6β-treated retinas. In all treated eyes, substantial rod-derived ERG signals were recorded as soon as 1 month post-injection (30% of normal eyes) and remained stable for at least 12 months (duration of the study). They were undetectable in untreated contralateral eyes. Most importantly, dim light vision was restored in all treated dogs.

Conclusions: : These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of progressive photoreceptor defects, the rcd1 dog.

Keywords: gene transfer/gene therapy • retina • photoreceptors 
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×