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Gene Ther. 2014 Apr;21(4):450-6. doi: 10.1038/gt.2014.8. Epub 2014 Feb 27.

Efficient gene delivery to the cone-enriched pig retina by dual AAV vectors.

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Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Department of Ophthalmology, Second University of Naples, Naples, Italy.
Department of Veterinary Morphophysiology and Animal Production, University of Bologna, Bologna, Italy.
1] Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy [2] Medical Genetics, Department of Translational Medicine, Federico II University, Naples, Italy.


Gene therapy with adeno-associated viral (AAV) vectors is limited by AAV cargo capacity that prevents their application to the inherited retinal diseases (IRDs), such as Stargardt disease (STGD) or Usher syndrome type IB (USH1B), which are due to mutations in genes larger than 5 kb. Trans-splicing or hybrid dual AAV vectors have been successfully exploited to reconstitute large gene expression in the mouse retina. Here, we tested them in the large cone-enriched pig retina that closely mimics the human retina. We found that dual AAV trans-splicing and hybrid vectors transduce pig photoreceptors, the major cell targets for treatment of IRDs, to levels that were about two- to threefold lower than those obtained with a single AAV vector of normal size. This efficiency is significantly higher than that in mice, and is potentially due to the high levels of dual AAV co-transduction we observe in pigs. We also show that subretinal delivery in pigs of dual AAV trans-splicing and hybrid vectors successfully reconstitute, albeit at variable levels, the expression of the large genes ABCA4 and MYO7A mutated in STGD and USH1B, respectively. Our data support the potential of dual AAV vectors for large gene reconstitution in the cone-enriched pig retina that is a relevant preclinical model.

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