Breuel, Saskia and Vorm, Mariann and Bräuer, Anja U. and Owczarek-Lipska, Marta and Neidhardt, John (2019) Combining engineered U1 snRNA and antisense oligonucleotides to improve the treatment of a BBS1 splice site mutation. Molecular Therapy / Nucleic Acids, 17. pp. 123-130. ISSN 2162-2531

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Manipulation of pre-mRNA processing is a promising approach toward overcoming disease-causing mutations and treating human diseases. We show that a combined treatment applying two splice-manipulating technologies improves therapeutic efficacies to correct mutation-induced splice defects. Previously, we identified a family affected by retinitis pigmentosa caused by the homozygous BBS1 splice donor site mutation c.479G > A. The mutation leads to both exon 5 skipping and intron 5 retention. We developed a therapeutic approach applying lentivirus-mediated gene delivery of engineered U1 small nuclear RNA (U1), which resulted in increased levels of correctly spliced BBS1. Herein, we show that the therapeutic effect of the engineered U1 efficiently reverted exon skipping but failed to reduce the intron retention. To complement the engineered U1 treatment, we identified four different antisense oligonucleotides (AONs) that block intron 5 retention in BBS1 transcripts. A treatment using engineered U1 in combination with AONs showed the highest therapeutic efficacy and increased the amount of correctly spliced BBS1 transcripts. We did not detect elevated levels of apoptotic cell death in AON-treated cell lines. In conclusion, engineered U1 or AONs provide efficient therapies with complementary effects and can be combined to increase efficacy of therapeutic approaches to correct splice defects.

Item Type: Article
Uncontrolled Keywords: AON; BBS1; Bardet-Biedl Syndrome 1; U1 snRNA; antisense oligonucleotide; gene therapy; genetic therapy; mutation; splice defect; splicing
Subjects: Technology, medicine, applied sciences > Medicine and health
Divisions: Faculty of Medicine and Health Sciences > Department of Human Medicine
Date Deposited: 12 Mar 2020 11:23
Last Modified: 12 Mar 2020 11:23
URN: urn:nbn:de:gbv:715-oops-44447
DOI: 10.1016/j.omtn.2019.08.014

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