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AAV8(Y733F)-mediated gene therapy in a Spata7 knockout mouse model of Leber congenital amaurosis and retinitis pigmentosa

Gene Therapy volume 22, pages 619–627 (2015)Cite this article

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Abstract

Loss of SPATA7 function causes the pathogenesis of Leber congenital amaurosis and retinitis pigmentosa. Spata7 knockout mice mimic human SPATA7–related retinal disease with apparent photoreceptor degeneration observed as early as postnatal day 15 (P15). To test the efficacy of adeno-associated virus (AAV)-mediated gene therapy for rescue of photoreceptor survival and function in Spata7 mutant mice, we employed the AAV8(Y733F) vector carrying hGRK1-driven full-length FLAG-tagged Spata7 cDNA to target both rod and cone photoreceptors. Following subretinal injection of this vector, FLAG-tagged SPATA7 was found to colocalize with endogenous SPATA7 in wild-type mice. In Spata7 mutant mice initially treated at P15, we observed improvement of photoresponse, photoreceptor ultrastructure and significant alleviation of photoreceptor degeneration. Furthermore, we performed treatments at P28 and P56 and found that all treatments (P15-P56) can ameliorate rod and cone loss in the long term (1 year); however, none efficiently protect photoreceptors from degeneration by 86 weeks of age as only a small amount of treated photoreceptors can survive to this time. This study demonstrates long-term improvement of photoreceptor function by AAV8(Y733F)-introduced Spata7 expression in a mouse model as potential treatment of the human disease, but also suggests that treated mutant photoreceptors still undergo progressive degeneration.

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Acknowledgements

We thank Brandee Price and David L. Simons for instruction in subretinal injection and ERG assays and Debra Townley for assistance with TEM. We thank Lang Ma and Denise R. Archambeault for experimental help. This project is supported by NIH grants EY020540, EY018571 (GM and RC), EY021721 (WWH) and grants from the Retina Research Foundation (GM and RC), the Macula Vision Research Foundation (WWH), Foundation Fighting Blindness and Research to Prevent Blindness, Inc (WWH). This project was supported by the Integrated Microscopy Core at Baylor College of Medicine with funding from the NIH (HD007495, DK56338, and CA125123), the Dan L. Duncan Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.

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Authors and Affiliations

  1. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

    H Zhong, Y Moayedi & G Mardon

  2. HGSC, Baylor College of Medicine, Houston, TX, USA

    A Eblimit, Y Chen, Y Li & R Chen

  3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    A Eblimit, Y Chen, Y Li, R Chen & G Mardon

  4. Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA

    Y Moayedi & G Mardon

  5. Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA

    S L Boye, V A Chiodo & W W Hauswirth

  6. Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA

    R M Nichols & G Mardon

  7. Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA

    R Chen & G Mardon

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  1. H Zhong
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  2. A Eblimit
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  3. Y Moayedi
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  4. S L Boye
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  7. Y Li
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  8. R M Nichols
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  9. W W Hauswirth
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  10. R Chen
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Corresponding author

Correspondence to G Mardon.

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Competing interests

The University of Florida and WWH have a financial interest in the use of AAV therapies and own equity in a company (AGTC Inc.) that might, in the future, commercialize some aspects of this work. The remaining authors declare no conflict of interest.

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Zhong, H., Eblimit, A., Moayedi, Y. et al. AAV8(Y733F)-mediated gene therapy in a Spata7 knockout mouse model of Leber congenital amaurosis and retinitis pigmentosa. Gene Ther 22, 619–627 (2015). https://doi.org/10.1038/gt.2015.42

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