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Journal of Virology, October 2007, p. 11372-11380, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.01327-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Novel Adeno-Associated Virus Serotypes Efficiently Transduce Murine Photoreceptors{triangledown}

Mariacarmela Allocca,1,2 Claudio Mussolino,1,2 Maria Garcia-Hoyos,1 Daniela Sanges,3 Carolina Iodice,1 Marco Petrillo,1 Luk H. Vandenberghe,4 James M. Wilson,4 Valeria Marigo,3 Enrico M. Surace,1* and Alberto Auricchio1,5*

Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy,1 SEMM, European School of Molecular Medicine, Naples, Italy,2 Department of Biomedical Sciences, University of Modena and Reggio Emilia, Reggio Emilia, Italy,3 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,4 Medical Genetics, Department of Pediatrics, Federico II University, Naples, Italy5

Received 18 June 2007/ Accepted 1 August 2007

Severe inherited retinal diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are caused by mutations in genes preferentially expressed in photoreceptors. While adeno-associated virus (AAV)-mediated gene transfer can correct retinal pigment epithelium (RPE) defects in animal models, approaches for the correction of photoreceptor-specific diseases are less efficient. We evaluated the ability of novel AAV serotypes (AAV2/7, AAV2/8, AAV2/9, AAV2rh.43, AAV2rh.64R1, and AAV2hu.29R) in combination with constitutive or photoreceptor-specific promoters to improve photoreceptor transduction, a limiting step in photoreceptor rescue. Based on a qualitative analysis, all AAV serotypes tested efficiently transduce the RPE as well as rod and cone photoreceptors after subretinal administration in mice. Interestingly, AAV2/9 efficiently transduces Müller cells. To compare photoreceptor transduction from different AAVs and promoters in both a qualitative and quantitative manner, we designed a strategy based on the use of a bicistronic construct expressing both enhanced green fluorescent protein and luciferase. We found that AAV2/8 and AAV2/7 mediate six- to eightfold higher levels of in vivo photoreceptor transduction than AAV2/5, considered so far the most efficient AAV serotype for photoreceptor targeting. In addition, following subretinal administration of AAV, the rhodopsin promoter allows significantly higher levels of photoreceptor expression than the other ubiquitous or photoreceptor-specific promoters tested. Finally, we show that AAV2/7, AAV2/8, and AAV2/9 outperform AAV2/5 following ex vivo transduction of retinal progenitor cells differentiated into photoreceptors. We conclude that AAV2/7 or AAV2/8 and the rhodopsin promoter provide the highest levels of photoreceptor transduction both in and ex vivo and that this may overcome the limitation to therapeutic success observed so far in models of inherited severe photoreceptor diseases.

* Corresponding author. Mailing address: Telethon Institute of Genetics and Medicine, Via P. Castellino, 111, 80131 Napoli, Italy. Phone: 11-39-081-6132229. Fax: 11-39-081-5790919. E-mail for E. M. Surace: surace{at}tigem.it. E-mail for A. Auricchio: auricchio{at}tigem.it

{triangledown} Published ahead of print on 15 August 2007.

Journal of Virology, October 2007, p. 11372-11380, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.01327-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Tan, M. H., Smith, A. J., Pawlyk, B., Xu, X., Liu, X., Bainbridge, J. B., Basche, M., McIntosh, J., Tran, H. V., Nathwani, A., Li, T., Ali, R. R. (2009). Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors. Hum Mol Genet 18: 2099-2114 [Abstract] [Full Text]  


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