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Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy

Gene Therapy volume 12, pages 694–701 (2005)Cite this article

Abstract

The Royal College of Surgeons (RCS) rat is a well-characterized model of autosomal recessive retinitis pigmentosa (RP) due to a defect in the retinal pigment epithelium (RPE). It is homozygous for a null mutation in the gene encoding , a receptor tyrosine kinase found in RPE cells, that is required for phagocytosis of shed photoreceptor outer segments. The absence of Mertk results in accumulation of outer segment debris. This subsequently leads to progressive loss of photoreceptor cells. In order to evaluate the efficacy of lentiviral-mediated gene replacement therapy in the RCS rat, we produced recombinant VSV-G pseudotyped HIV-1-based lentiviruses containing a murine Mertk cDNA driven by a spleen focus forming virus (SFFV) promoter. The vector was subretinally injected into the right eye of 10-day-old RCS rats; the left eye was left untreated as an internal control. Here, we present a detailed assessment of the duration and extent of the morphological rescue and the resulting functional benefits. We examined animals at various time points over a period of 7 months by light and electron microscopy, and electroretinography. We observed correction of the phagocytic defect, slowing of photoreceptor cell loss and preservation of retinal function for up to 7 months. This study demonstrates the potential of gene therapy approaches for the treatment of retinal degenerations caused by defects specific to the RPE and supports the use of lentiviral vectors for the treatment of such disorders.

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Acknowledgements

This work was supported by grants from the British Retinitis Pigmentosa Society and the Sir Jules Thorn Charitable Trust.

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Authors and Affiliations

  1. Division of Molecular Therapy, Institute of Ophthalmology, University College London, UK

    M Tschernutter, F C Schlichtenbrede, K S Balaggan, P M Munro, J W B Bainbridge, A J Smith & R R Ali

  2. Molecular Immunology Unit, Institute of Child Health, University College London, UK

    S Howe, A J Thrasher & R R Ali

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  1. M Tschernutter
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  2. F C Schlichtenbrede
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  3. S Howe
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  4. K S Balaggan
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  5. P M Munro
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  7. A J Thrasher
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  8. A J Smith
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  9. R R Ali
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Tschernutter, M., Schlichtenbrede, F., Howe, S. et al. Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy. Gene Ther 12, 694–701 (2005). https://doi.org/10.1038/sj.gt.3302460

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  • DOI: https://doi.org/10.1038/sj.gt.3302460

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