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Enhanced gene delivery to the neonatal retina through systemic administration of tyrosine-mutated AAV9

Gene Therapy volume 19, pages 176–181 (2012)Cite this article

Abstract

Delivery of therapeutic genes to a large region of the retina with minimal damage from intraocular surgery is a central goal of treatment for retinal degenerations. Recent studies have shown that AAV9 can reach the central nervous system (CNS) and retina when administered systemically to neonates, which is a promising strategy for some retinal diseases. We investigated whether the retinal transduction efficiency of systemically delivered AAV9 could be improved by mutating capsid surface tyrosines, previously shown to increase the infectivity of several AAV vectors. Specifically, we evaluated retinal transduction following neonatal intravascular administration of AAV9 vectors containing tyrosine to phenylalanine mutations at two highly conserved sites. Our results show that a novel, double tyrosine mutant of AAV9 significantly enhanced gene delivery to the CNS and retina, and that gene expression can be restricted to rod photoreceptor cells by incorporating a rhodopsin promoter. This approach provides a new methodology for the development of retinal gene therapies or creation of animal models of neurodegenerative disease.

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Acknowledgements

We thank Ryan Klimczak for performing the site-directed mutagenesis to generate the AAV9 single and double tyrosine mutants. We also thank Dr Alberto Auricchio for sharing the AAV-rho-GFP plasmid. This work was supported by grants from the NIH Nanomedicine Development Center for the Optical Control of Biological Function (PN2EY018241), the Foundation Fighting Blindness USA and the NIH grant RC2NS069476.

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Authors and Affiliations

  1. Department of Chemical Engineering, The Helen Wills Neuroscience Institute, The University of California, Berkeley, CA, USA

    D Dalkara & D V Schaffer

  2. Department of Bioengineering, The Helen Wills Neuroscience Institute, The University of California, Berkeley, CA, USA

    D Dalkara & D V Schaffer

  3. Department of Molecular and Cellular Biology, The Helen Wills Neuroscience Institute, The University of California, Berkeley, CA, USA

    L C Byrne, T Lee, N V Hoffmann & J G Flannery

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  1. D Dalkara
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  2. L C Byrne
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  3. T Lee
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  4. N V Hoffmann
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  5. D V Schaffer
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  6. J G Flannery
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Corresponding author

Correspondence to D Dalkara.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on Gene Therapy website

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Dalkara, D., Byrne, L., Lee, T. et al. Enhanced gene delivery to the neonatal retina through systemic administration of tyrosine-mutated AAV9. Gene Ther 19, 176–181 (2012). https://doi.org/10.1038/gt.2011.163

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