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

Autor: Giulia Mearini, Ingke Braren, Christina Gedicke-Hornung, Saskia Schlossarek, Stéphanie Lorain, Guillaume Précigout, Thomas Voit, Verena Behrens-Gawlik, Birgit Geertz, Patrick A. Dreyfus, Lucie Carrier, Florian Weinberger, Silke Reischmann, Doreen Stimpel, Luis Garcia, Thomas Eschenhagen
Přispěvatelé: Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HAL UPMC, Gestionnaire
Jazyk: angličtina
Rok vydání: 2013
Předmět:
antisense oligoribonucleotide
Cardiomyopathy
030204 cardiovascular system & hematology
Biology
medicine.disease_cause
Adenoviridae
03 medical and health sciences
Exon
Mice
alternative splicing
cardiac myosin- binding protein-C
0302 clinical medicine
[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Transduction
Genetic
Gene knockin
RNA
Small Nuclear
medicine
Animals
Humans
Protein Isoforms
Gene Knock-In Techniques
RNA
Messenger
cardiac myosin-binding protein-C
Research Articles
030304 developmental biology
0303 health sciences
Messenger RNA
Myocardium
Alternative splicing
Heart
Exons
Genetic Therapy
Cardiomyopathy
Hypertrophic
medicine.disease
hypertrophic cardiomyopathy
Molecular biology
Exon skipping
3. Good health
[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
HEK293 Cells
RNA splicing
Mutation
Cancer research
Molecular Medicine
Hypertrophy
Left Ventricular
Carrier Proteins
Oligoribonucleotides
Antisense
exon skipping
Zdroj: EMBO Molecular Medicine
EMBO Molecular Medicine, 2013, 5 (7), pp.1128-1145. ⟨10.1002/emmm.201202168⟩
EMBO Molecular Medicine, Wiley Open Access, 2013, 5 (7), pp.1128-1145. ⟨10.1002/emmm.201202168⟩
EMBO Molecular Medicine; Vol 5
ISSN: 1757-4676
1757-4684
Popis: International audience; 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-5þ6). Transduction of cardiac myocytes or systemic administration of AAV-U7-AON-5þ6 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.
Databáze: OpenAIRE
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