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Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations

Gene Therapy volume 17, pages 117–131 (2010)Cite this article

Abstract

Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is required for the biosynthesis of photoreceptor phosphodiesterase (PDE). Gene defects in AIPL1 cause a heterogeneous set of conditions ranging from Leber's congenital amaurosis (LCA), the severest form of early-onset retinal degeneration, to milder forms such as retinitis pigmentosa (RP) and cone-rod dystrophy. In mice, null and hypomorphic alleles cause retinal degeneration similar to human LCA and RP, respectively. Thus these mouse models represent two ends of the disease spectrum associated with AIPL1 gene defects in humans. We evaluated whether adeno-associated virus (AAV)-mediated gene replacement therapy in these models could restore PDE biosynthesis in rods and cones and thereby improve photoreceptor survival. We validated the efficacy of human AIPL1 (isoform 1) replacement gene controlled by a promoter derived from the human rhodopsin kinase (RK) gene, which is active in both rods and cones. We found substantial and long-term rescue of the disease phenotype as a result of transgene expression. This is the first gene therapy study in which both rods and cones were targeted successfully with a single photoreceptor-specific promoter. We propose that the vector and construct design used in this study could serve as a prototype for a human clinical trial.

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Acknowledgements

We thank Dr Michael Dyer (St Jude Children's Research Hospital, Memphis, TN, USA) for providing the Aipl1−/− mice, Dr Visvanathan Ramamurthy (West Virginia University, Morgantown, WV, SA) for human AIPL1 antiserum, Norman Michaud (Massachusetts Eye & Ear Histology Core) for a portion of the histology processing and Dr Jeng-Shin Lee (the Research Vector Core, Harvard Medical School) for AAV vector packaging. This work was supported by National Eye Institute Grant EY10581, NEI core grant for Vision Research (P30EY14104), the Foundation Fighting Blindness, the Foundation for Retina Research, the Macular Vision Research Foundation, the Massachusetts Lions Eye Research Fund and by grants from the European Union (AAVEYE), the UK Department of Health and National Institute of Health Research BMRC for Ophthalmology.

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  1. X Sun and B Pawlyk: These authors contributed equally to this work.

Authors and Affiliations

  1. Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA

    X Sun, B Pawlyk, X Xu, X Liu, O V Bulgakov, M Adamian, M A Sandberg & T Li

  2. Schepens Eye Research Institute, Harvard Medical School, Boston, MA, USA

    S C Khani

  3. Department of Genetics, Institute of Ophthalmology, NIHR Biomedical Research Centre, University College London, London, UK

    M-H Tan, A J Smith & R R Ali

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Correspondence to T Li.

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Sun, X., Pawlyk, B., Xu, X. et al. Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations. Gene Ther 17, 117–131 (2010). https://doi.org/10.1038/gt.2009.104

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  • DOI: https://doi.org/10.1038/gt.2009.104

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