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Int. J. Mol. Sci. 2018, 19(3), 753; https://doi.org/10.3390/ijms19030753

Antisense Oligonucleotide-Based Splicing Correction in Individuals with Leber Congenital Amaurosis due to Compound Heterozygosity for the c.2991+1655A>G Mutation in CEP290

1
Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
2
The Rotterdam Eye Hospital, 3011 BH Rotterdam, The Netherlands
3
Human Genetics, Faculty of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany
4
Research Center Neurosensory Science, University Oldenburg, 26129 Oldenburg, Germany
5
Department of Ophthalmology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
6
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
7
Department of Ophthalmology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Received: 31 January 2018 / Revised: 2 March 2018 / Accepted: 5 March 2018 / Published: 7 March 2018
(This article belongs to the Special Issue Pre-mRNA Splicing 2017)
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Abstract

Leber congenital amaurosis (LCA) is a rare inherited retinal disorder affecting approximately 1:50,000 people worldwide. So far, mutations in 25 genes have been associated with LCA, with CEP290 (encoding the Centrosomal protein of 290 kDa) being the most frequently mutated gene. The most recurrent LCA-causing CEP290 mutation, c.2991+1655A>G, causes the insertion of a pseudoexon into a variable proportion of CEP290 transcripts. We previously demonstrated that antisense oligonucleotides (AONs) have a high therapeutic potential for patients homozygously harbouring this mutation, although to date, it is unclear whether rescuing one single allele is enough to restore CEP290 function. Here, we assessed the AON efficacy at RNA, protein and cellular levels in samples that are compound heterozygous for this mutation, together with a protein-truncating mutation in CEP290. We demonstrate that AONs can efficiently restore splicing and increase protein levels. However, due to a high variability in ciliation among the patient-derived cell lines, the efficacy of the AONs was more difficult to assess at the cellular level. This observation points towards the importance of the severity of the second allele and possibly other genetic variants present in each individual. Overall, AONs seem to be a promising tool to treat CEP290-associated LCA, not only in homozygous but also in compound heterozygous carriers of the c.2991+1655A>G variant. View Full-Text
Keywords: CEP290; antisense oligonucleotides; splicing correction; compound heterozygosity; Leber congenital amaurosis CEP290; antisense oligonucleotides; splicing correction; compound heterozygosity; Leber congenital amaurosis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Duijkers, L.; van den Born, L.I.; Neidhardt, J.; Bax, N.M.; Pierrache, L.H.M.; Klevering, B.J.; Collin, R.W.J.; Garanto, A. Antisense Oligonucleotide-Based Splicing Correction in Individuals with Leber Congenital Amaurosis due to Compound Heterozygosity for the c.2991+1655A>G Mutation in CEP290. Int. J. Mol. Sci. 2018, 19, 753.

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