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000276937 037__ $$aDKFZ-2023-01214
000276937 041__ $$aEnglish
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000276937 1001_ $$aToms, Maria$$b0
000276937 245__ $$aSuccessful large gene augmentation of USH2A with non-viral episomal vectors.
000276937 260__ $$aNew York, NY$$bNature Publ. Group$$c2023
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000276937 500__ $$a2023 Sep 6;31(9):2755-2766
000276937 520__ $$aUSH2A mutations are a common cause of autosomal recessive retinitis pigmentosa (RP) and Usher syndrome, for which there are currently no approved treatments. Gene augmentation is a valuable therapeutic strategy for treating many inherited retinal diseases, however conventional adeno-associated virus (AAV) gene therapy cannot accommodate cDNAs exceeding 4.7kb, such as the 15.6kb-long USH2A coding sequence. In the present study, we adopted an alternative strategy to successfully generate scaffold/matrix attachment region (S/MAR) DNA plasmid vectors containing the full-length human USH2A coding sequence, a GFP reporter gene and a ubiquitous promoter (CMV or CAG), reaching a size of approximately 23kb. We assessed the vectors in transfected HEK-293 cells and USH2A patient-derived dermal fibroblasts, in addition to ush2au507 zebrafish microinjected with the vector at the one-cell stage. pS/MAR-USH2A vectors drove persistent transgene expression in patient fibroblasts with restoration of usherin. Twelve months of GFP expression was detected in the photoreceptor cells, with rescue of Usher 2 complex localisation in the photoreceptors of ush2au507 zebrafish retina injected with pS/MAR-USH2A. To our knowledge, this is the first reported vector which can be used to express full-length usherin with functional rescue. S/MAR DNA vectors have shown promise as a novel non-viral retinal gene therapy, warranting further translational development.
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000276937 7001_ $$aToualbi, Lyes$$b1
000276937 7001_ $$0P:(DE-HGF)0$$aAlmeida, Patrick V$$b2
000276937 7001_ $$0P:(DE-He78)15dff5647002b4dcfe892b251cd14b62$$aHarbottle, Richard$$b3$$udkfz
000276937 7001_ $$aMoosajee, Mariya$$b4
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