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Mol Ther Nucleic Acids. 2016 Nov 1;5(10):e381. doi: 10.1038/mtna.2016.89.

Antisense Oligonucleotide-based Splice Correction for USH2A-associated Retinal Degeneration Caused by a Frequent Deep-intronic Mutation.

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Department of Otorhinolaryngology, Radboudumc, Nijmegen, the Netherlands.
Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, the Netherlands.
Laboratoire de Génétique Moléculaire, CHU Montpellier, Montpellier, France.
Laboratoire de Génétique de Maladies Rares EA 7402, Université de Montpellier, Montpellier, France.
Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, the Netherlands.
Radboud Institute for Health Sciences, Radboudumc, Nijmegen, the Netherlands.
Grupo de Investigación en Biomedicina Molecular, Celular y Genómica, and CIBERER, Madrid, Spain.
Department of Human Genetics, Radboudumc, Nijmegen, the Netherlands.


Usher syndrome (USH) is the most common cause of combined deaf-blindness in man. The hearing loss can be partly compensated by providing patients with hearing aids or cochlear implants, but the loss of vision is currently untreatable. In general, mutations in the USH2A gene are the most frequent cause of USH explaining up to 50% of all patients worldwide. The first deep-intronic mutation in the USH2A gene (c.7595-2144A>G) was reported in 2012, leading to the insertion of a pseudoexon (PE40) into the mature USH2A transcript. When translated, this PE40-containing transcript is predicted to result in a truncated non-functional USH2A protein. In this study, we explored the potential of antisense oligonucleotides (AONs) to prevent aberrant splicing of USH2A pre-mRNA as a consequence of the c.7595-2144A>G mutation. Engineered 2'-O-methylphosphorothioate AONs targeting the PE40 splice acceptor site and/or exonic splice enhancer regions displayed significant splice correction potential in both patient derived fibroblasts and a minigene splice assay for USH2A c.7595-2144A>G, whereas a non-binding sense oligonucleotide had no effect on splicing. Altogether, AON-based splice correction could be a promising approach for the development of a future treatment for USH2A-associated retinitis pigmentosa caused by the deep-intronic c.7595-2144A>G mutation.

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