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Retinal transduction profiles by high-capacity viral vectors

Gene Therapy volume 21, pages 855–865 (2014)Cite this article

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Abstract

Retinal gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. However, the limited cargo capacity of AAV prevents their use for therapy of those inherited retinopathies (IRs) due to mutations in large (>5 kb) genes. Viral vectors derived from adenovirus (Ad), lentivirus (LV) and herpes virus (HV) can package large DNA sequences, but do not target efficiently retinal photoreceptors (PRs) where the majority of genes responsible for IRs are expressed. Here, we have evaluated the mouse retinal transduction profiles of vectors derived from 16 different Ad serotypes, 7 LV pseudotypes and from a bovine HV. Most of the vectors tested transduced efficiently the retinal pigment epithelium. We found that LV-GP64 tends to transduce more PRs than the canonical LV-VSVG, albeit this was restricted to a narrow region. We observed more extensive PR transduction with HdAd1, 2 and 5/F35++ than with LV, although none of them outperformed the canonical HdAd5 or matched the extension of PR transduction achieved with AAV2/8.

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Acknowledgements

We thank the TIGEM AAV Vector Core for AAV vector production and the TIGEM Ad Vector Core for expanding some adenoviral preps and providing some Ad controls (see Materials and Methods for details). We are also grateful to Graciana Diez-Roux for the critical reading of this manuscript. This work was supported by the European Research Council/ERC Grant agreement n 282085 ‘RetGeneTx’; the NIH (grant R24 EY019861-01 A); the Italian Telethon Foundation (grant TGM11MT1).

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Authors and Affiliations

  1. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

    A Puppo, G Cesi, E Marrocco, P Piccolo, N Brunetti-Pierri & A Auricchio

  2. Department of Medical Veterinary Science, University of Parma, Parma, Italy

    S Jacca & G Donofrio

  3. Departments of Pediatrics and Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA

    D M Shayakhmetov

  4. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada

    R J Parks

  5. Departments of Internal Medicine, Neurology and Molecular Physiology & Biophysics, University of Iowa, Iowa City, IA, USA

    B L Davidson

  6. Okairos, Rome, Italy

    S Colloca

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

    P Ng

  8. Department of Translational Medicine, Medical Genetics, University of Naples Federico II, Naples, Italy

    A Auricchio

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  1. A Puppo
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Puppo, A., Cesi, G., Marrocco, E. et al. Retinal transduction profiles by high-capacity viral vectors. Gene Ther 21, 855–865 (2014). https://doi.org/10.1038/gt.2014.57

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