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RPE65 gene therapy slows cone loss in Rpe65-deficient dogs

Gene Therapy volume 20, pages 545–555 (2013)Cite this article

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Abstract

Recent clinical trials of retinal pigment epithelium gene (RPE65) supplementation therapy in Leber congenital amaurosis type 2 patients have demonstrated improvements in rod and cone function, but it may be some years before the effects of therapy on photoreceptor survival become apparent. The Rpe65-deficient dog is a very useful pre-clinical model in which to test efficacy of therapies, because the dog has a retina with a high degree of similarity to that of humans. In this study, we evaluated the effect of RPE65 gene therapy on photoreceptor survival in order to predict the potential benefit and limitations of therapy in patients. We examined the retinas of Rpe65-deficient dogs after RPE65 gene therapy to evaluate the preservation of rods and cone photoreceptor subtypes. We found that gene therapy preserves both rods and cones. While the moderate loss of rods in the Rpe65-deficient dog retina is slowed by gene therapy, S-cones are lost extensively and gene therapy can prevent that loss, although only within the treated area. Although LM-cones are not lost extensively, cone opsin mislocalization indicates that they are stressed, and this can be partially reversed by gene therapy. Our results suggest that gene therapy may be able to slow cone degeneration in patients if intervention is sufficiently early and also that it is probably important to treat the macula in order to preserve central function.

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Acknowledgements

This work was funded by the British Retinitis Pigmentosa Society, Midwest Eye Banks and Transplantation Center Research Program, The Hal and Jean Glassen Memorial Foundation, Myers-Dunlap Endowment for Canine Health and MSU College of Veterinary Medicine Purebred Dog Endowment Fund. RRA and JWB are investigators at The NIHR Center for Ophthalmology at UCL and Moorfields Eye Hospital. We acknowledge Janice Querubin for providing veterinary technician expertise and Cheri Johnson for assistance with canine reproduction. We thank Cheryl Sisk and Ray Figuera for assisting with cryostat use.

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  1. Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA

    F M Mowat, A R Breuwer, J T Bartoe, M J Annear & S M Petersen-Jones

  2. Department of Genetics, UCL Institute of Ophthalmology, London, UK

    F M Mowat, A J Smith, J W B Bainbridge & R R Ali

  3. Center for Statistical Training and Consulting, Michigan State University, East Lansing, MI, USA

    Z Zhang

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  1. F M Mowat
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Mowat, F., Breuwer, A., Bartoe, J. et al. RPE65 gene therapy slows cone loss in Rpe65-deficient dogs. Gene Ther 20, 545–555 (2013). https://doi.org/10.1038/gt.2012.63

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