| Literature DB >> 31092694 |
Patrizia Tornabene1, Ivana Trapani1,2, Renato Minopoli1, Miriam Centrulo1, Mariangela Lupo1, Sonia de Simone1, Paola Tiberi1, Fabio Dell'Aquila1, Elena Marrocco1, Carolina Iodice1, Antonella Iuliano1, Carlo Gesualdo3, Settimio Rossi3, Laura Giaquinto1, Silvia Albert4, Carel B Hoyng5, Elena Polishchuk1, Frans P M Cremers5, Enrico M Surace1,2, Francesca Simonelli3, Maria A De Matteis1,6, Roman Polishchuk1, Alberto Auricchio7,8.
Abstract
Retinal gene therapy with adeno-associated viral (AAV) vectors holds promises for treating inherited and noninherited diseases of the eye. Although clinical data suggest that retinal gene therapy is safe and effective, delivery of large genes is hindered by the limited AAV cargo capacity. Protein trans-splicing mediated by split inteins is used by single-cell organisms to reconstitute proteins. Here, we show that delivery of multiple AAV vectors each encoding one of the fragments of target proteins flanked by short split inteins results in protein trans-splicing and full-length protein reconstitution in the retina of mice and pigs and in human retinal organoids. The reconstitution of large therapeutic proteins using this approach improved the phenotype of two mouse models of inherited retinal diseases. Our data support the use of split intein-mediated protein trans-splicing in combination with AAV subretinal delivery for gene therapy of inherited blindness due to mutations in large genes.Entities:
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Year: 2019 PMID： 31092694 PMCID： PMC6863751 DOI： 10.1126/scitranslmed.aav4523
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 19.319