Publication

Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation

Breuel, S., Vorm, M., Braeuer, A. U., Owczarek-Lipska, M. & Neidhardt, J., 6-Dec-2019, In : Molecular therapy - Nucleic acids. 18, p. 123-130 8 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Breuel, S., Vorm, M., Braeuer, A. U., Owczarek-Lipska, M., & Neidhardt, J. (2019). Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation. Molecular therapy - Nucleic acids, 18, 123-130. https://doi.org/10.1016/j.omtn.2019.08.014

Author

Breuel, Saskia ; Vorm, Mariann ; Braeuer, Anja U. ; Owczarek-Lipska, Marta ; Neidhardt, John. / Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation. In: Molecular therapy - Nucleic acids. 2019 ; Vol. 18. pp. 123-130.

Harvard

Breuel, S, Vorm, M, Braeuer, AU, Owczarek-Lipska, M & Neidhardt, J 2019, 'Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation', Molecular therapy - Nucleic acids, vol. 18, pp. 123-130. https://doi.org/10.1016/j.omtn.2019.08.014

Standard

Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation. / Breuel, Saskia; Vorm, Mariann; Braeuer, Anja U.; Owczarek-Lipska, Marta; Neidhardt, John.

In: Molecular therapy - Nucleic acids, Vol. 18, 06.12.2019, p. 123-130.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Breuel S, Vorm M, Braeuer AU, Owczarek-Lipska M, Neidhardt J. Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation. Molecular therapy - Nucleic acids. 2019 Dec 6;18:123-130. https://doi.org/10.1016/j.omtn.2019.08.014


BibTeX

@article{21dec3c20da84d248de2a1b764bb28b8,
title = "Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation",
abstract = "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.",
keywords = "BARDET-BIEDL-SYNDROME, SMALL NUCLEAR-RNA, GENE THERAPEUTIC APPROACH, CORRECT, RESCUE, DEFECTS, EXPRESSION, STRATEGY, DISEASE, VECTOR",
author = "Saskia Breuel and Mariann Vorm and Braeuer, {Anja U.} and Marta Owczarek-Lipska and John Neidhardt",
year = "2019",
month = "12",
day = "6",
doi = "10.1016/j.omtn.2019.08.014",
language = "English",
volume = "18",
pages = "123--130",
journal = "Molecular therapy - Nucleic acids",
issn = "2162-2531",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation

AU - Breuel, Saskia

AU - Vorm, Mariann

AU - Braeuer, Anja U.

AU - Owczarek-Lipska, Marta

AU - Neidhardt, John

PY - 2019/12/6

Y1 - 2019/12/6

N2 - 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.

AB - 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.

KW - BARDET-BIEDL-SYNDROME

KW - SMALL NUCLEAR-RNA

KW - GENE THERAPEUTIC APPROACH

KW - CORRECT

KW - RESCUE

KW - DEFECTS

KW - EXPRESSION

KW - STRATEGY

KW - DISEASE

KW - VECTOR

U2 - 10.1016/j.omtn.2019.08.014

DO - 10.1016/j.omtn.2019.08.014

M3 - Article

VL - 18

SP - 123

EP - 130

JO - Molecular therapy - Nucleic acids

JF - Molecular therapy - Nucleic acids

SN - 2162-2531

ER -

ID: 109731830