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Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice

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Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice. / Hornung, Christina; Behrens, Verena; Reischmann, Silke; Geertz, Birgit; Stimpel, Doreen; Weinberger, Florian; Schlossarek, Saskia; Précigout, Guillaume; Braren, Ingke ; Eschenhagen, Thomas; Mearini, Giulia; Lorain, Stéphanie; Voit, Thomas; Dreyfus, Patrick A; Garcia, Luis; Carrier, Lucie.

In: EMBO MOL MED, Vol. 5, No. 7, 01.07.2013, p. 1060-77.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Hornung, C, Behrens, V, Reischmann, S, Geertz, B, Stimpel, D, Weinberger, F, Schlossarek, S, Précigout, G, Braren, I, Eschenhagen, T, Mearini, G, Lorain, S, Voit, T, Dreyfus, PA, Garcia, L & Carrier, L 2013, 'Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice', EMBO MOL MED, vol. 5, no. 7, pp. 1060-77. https://doi.org/10.1002/emmm.201202168

APA

Hornung, C., Behrens, V., Reischmann, S., Geertz, B., Stimpel, D., Weinberger, F., Schlossarek, S., Précigout, G., Braren, I., Eschenhagen, T., Mearini, G., Lorain, S., Voit, T., Dreyfus, P. A., Garcia, L., & Carrier, L. (2013). Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice. EMBO MOL MED, 5(7), 1060-77. https://doi.org/10.1002/emmm.201202168

Vancouver

Hornung C, Behrens V, Reischmann S, Geertz B, Stimpel D, Weinberger F et al. Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice. EMBO MOL MED. 2013 Jul 1;5(7):1060-77. https://doi.org/10.1002/emmm.201202168

Bibtex

@article{50fac7daa8664395958199188fab7f9c,
title = "Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice",
abstract = "Exon skipping mediated by antisense oligoribonucleotides (AON) is a promising therapeutic approach for genetic disorders, but has not yet been evaluated for cardiac diseases. We investigated the feasibility and efficacy of viral-mediated AON transfer in a Mybpc3-targeted knock-in (KI) mouse model of hypertrophic cardiomyopathy (HCM). KI mice carry a homozygous G>A transition in exon 6, which results in three different aberrant mRNAs. We identified an alternative variant (Var-4) deleted of exons 5-6 in wild-type and KI mice. To enhance its expression and suppress aberrant mRNAs we designed AON-5 and AON-6 that mask splicing enhancer motifs in exons 5 and 6. AONs were inserted into modified U7 small nuclear RNA and packaged in adeno-associated virus (AAV-U7-AON-5+6). Transduction of cardiac myocytes or systemic administration of AAV-U7-AON-5+6 increased Var-4 mRNA/protein levels and reduced aberrant mRNAs. Injection of newborn KI mice abolished cardiac dysfunction and prevented left ventricular hypertrophy. Although the therapeutic effect was transient and therefore requires optimization to be maintained over an extended period, this proof-of-concept study paves the way towards a causal therapy of HCM.",
keywords = "Adenoviridae, Alternative Splicing, Animals, Cardiomyopathy, Hypertrophic, Carrier Proteins, Exons, Gene Knock-In Techniques, Genetic Therapy, HEK293 Cells, Heart, Humans, Hypertrophy, Left Ventricular, Mice, Mutation, Myocardium, Oligoribonucleotides, Antisense, Protein Isoforms, RNA, Messenger, RNA, Small Nuclear, Transduction, Genetic",
author = "Christina Hornung and Verena Behrens and Silke Reischmann and Birgit Geertz and Doreen Stimpel and Florian Weinberger and Saskia Schlossarek and Guillaume Pr{\'e}cigout and Ingke Braren and Thomas Eschenhagen and Giulia Mearini and St{\'e}phanie Lorain and Thomas Voit and Dreyfus, {Patrick A} and Luis Garcia and Lucie Carrier",
note = "{\textcopyright} 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.",
year = "2013",
month = jul,
day = "1",
doi = "10.1002/emmm.201202168",
language = "English",
volume = "5",
pages = "1060--77",
journal = "EMBO MOL MED",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "7",

}

RIS

TY - JOUR

T1 - Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice

AU - Hornung, Christina

AU - Behrens, Verena

AU - Reischmann, Silke

AU - Geertz, Birgit

AU - Stimpel, Doreen

AU - Weinberger, Florian

AU - Schlossarek, Saskia

AU - Précigout, Guillaume

AU - Braren, Ingke

AU - Eschenhagen, Thomas

AU - Mearini, Giulia

AU - Lorain, Stéphanie

AU - Voit, Thomas

AU - Dreyfus, Patrick A

AU - Garcia, Luis

AU - Carrier, Lucie

N1 - © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

PY - 2013/7/1

Y1 - 2013/7/1

N2 - Exon skipping mediated by antisense oligoribonucleotides (AON) is a promising therapeutic approach for genetic disorders, but has not yet been evaluated for cardiac diseases. We investigated the feasibility and efficacy of viral-mediated AON transfer in a Mybpc3-targeted knock-in (KI) mouse model of hypertrophic cardiomyopathy (HCM). KI mice carry a homozygous G>A transition in exon 6, which results in three different aberrant mRNAs. We identified an alternative variant (Var-4) deleted of exons 5-6 in wild-type and KI mice. To enhance its expression and suppress aberrant mRNAs we designed AON-5 and AON-6 that mask splicing enhancer motifs in exons 5 and 6. AONs were inserted into modified U7 small nuclear RNA and packaged in adeno-associated virus (AAV-U7-AON-5+6). Transduction of cardiac myocytes or systemic administration of AAV-U7-AON-5+6 increased Var-4 mRNA/protein levels and reduced aberrant mRNAs. Injection of newborn KI mice abolished cardiac dysfunction and prevented left ventricular hypertrophy. Although the therapeutic effect was transient and therefore requires optimization to be maintained over an extended period, this proof-of-concept study paves the way towards a causal therapy of HCM.

AB - Exon skipping mediated by antisense oligoribonucleotides (AON) is a promising therapeutic approach for genetic disorders, but has not yet been evaluated for cardiac diseases. We investigated the feasibility and efficacy of viral-mediated AON transfer in a Mybpc3-targeted knock-in (KI) mouse model of hypertrophic cardiomyopathy (HCM). KI mice carry a homozygous G>A transition in exon 6, which results in three different aberrant mRNAs. We identified an alternative variant (Var-4) deleted of exons 5-6 in wild-type and KI mice. To enhance its expression and suppress aberrant mRNAs we designed AON-5 and AON-6 that mask splicing enhancer motifs in exons 5 and 6. AONs were inserted into modified U7 small nuclear RNA and packaged in adeno-associated virus (AAV-U7-AON-5+6). Transduction of cardiac myocytes or systemic administration of AAV-U7-AON-5+6 increased Var-4 mRNA/protein levels and reduced aberrant mRNAs. Injection of newborn KI mice abolished cardiac dysfunction and prevented left ventricular hypertrophy. Although the therapeutic effect was transient and therefore requires optimization to be maintained over an extended period, this proof-of-concept study paves the way towards a causal therapy of HCM.

KW - Adenoviridae

KW - Alternative Splicing

KW - Animals

KW - Cardiomyopathy, Hypertrophic

KW - Carrier Proteins

KW - Exons

KW - Gene Knock-In Techniques

KW - Genetic Therapy

KW - HEK293 Cells

KW - Heart

KW - Humans

KW - Hypertrophy, Left Ventricular

KW - Mice

KW - Mutation

KW - Myocardium

KW - Oligoribonucleotides, Antisense

KW - Protein Isoforms

KW - RNA, Messenger

KW - RNA, Small Nuclear

KW - Transduction, Genetic

U2 - 10.1002/emmm.201202168

DO - 10.1002/emmm.201202168

M3 - SCORING: Journal article

C2 - 23716398

VL - 5

SP - 1060

EP - 1077

JO - EMBO MOL MED

JF - EMBO MOL MED

SN - 1757-4676

IS - 7

ER -