期刊
EMBO MOLECULAR MEDICINE
卷 6, 期 2, 页码 194-211出版社
WILEY
DOI: 10.1002/emmm.201302948
关键词
AAV; ABCA4; gene therapy; MYO7A; retina
资金
- European Research Council/ERC [282085 RetGeneTx]
- European Community [242013 Treatrush]
- NIH [R24 RY019861-01A]
- Italian Telethon Foundation [TGM11MT1]
- Science Foundation Ireland (SFI)
- Health Research Board of Ireland/Fighting Blindness Ireland (MRCG)
Retinal gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. However, AAV's limited cargo capacity prevents its application to therapies of inherited retinal diseases due to mutations of genes over 5kb, like Stargardt's disease (STGD) and Usher syndrome type IB (USH1B). Previous methods based on forced' packaging of large genes into AAV capsids may not be easily translated to the clinic due to the generation of genomes of heterogeneous size which raise safety concerns. Taking advantage of AAV's ability to concatemerize, we generated dual AAV vectors which reconstitute a large gene by either splicing (trans-splicing), homologous recombination (overlapping), or a combination of the two (hybrid). We found that dual trans-splicing and hybrid vectors transduce efficiently mouse and pig photoreceptors to levels that, albeit lower than those achieved with a single AAV, resulted in significant improvement of the retinal phenotype of mouse models of STGD and USH1B. Thus, dual AAV trans-splicing or hybrid vectors are an attractive strategy for gene therapy of retinal diseases that require delivery of large genes.
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