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@ARTICLE{Toms:276937,
author = {M. Toms and L. Toualbi and P. V. Almeida$^*$ and R.
Harbottle$^*$ and M. Moosajee},
title = {{S}uccessful large gene augmentation of {USH}2{A} with
non-viral episomal vectors.},
journal = {Molecular therapy},
volume = {31},
number = {9},
issn = {1525-0016},
address = {New York, NY},
publisher = {Nature Publ. Group},
reportid = {DKFZ-2023-01214},
pages = {2755-2766},
year = {2023},
note = {2023 Sep 6;31(9):2755-2766},
abstract = {USH2A 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.},
cin = {F160},
ddc = {610},
cid = {I:(DE-He78)F160-20160331},
pnm = {316 - Infektionen, Entzündung und Krebs (POF4-316)},
pid = {G:(DE-HGF)POF4-316},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37337429},
doi = {10.1016/j.ymthe.2023.06.012},
url = {https://inrepo02.dkfz.de/record/276937},
}