Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes
Gene therapy is a promising option for severe forms of genetic diseases. We previously provided evidence for the feasibility of trans-splicing, exon skipping, and gene replacement in a mouse model of hypertrophic cardiomyopathy (HCM) carrying a mutation in MYBPC3, encoding cardiac myosin-binding pro...
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| Hauptverfasser: | , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
16 June 2017
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| In: |
Molecular therapy. Nucleic Acids
Year: 2017, Jahrgang: 7, Pages: 475-486 |
| ISSN: | 2162-2531 |
| DOI: | 10.1016/j.omtn.2017.05.008 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1016/j.omtn.2017.05.008 Verlag, kostenfrei, Volltext: http://www.sciencedirect.com/science/article/pii/S2162253117301798 
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| Verfasserangaben: | Maksymilian Prondzynski, Elisabeth Krämer, Sandra D. Laufer, Aya Shibamiya, Ole Pless, Frederik Flenner, Oliver J. Müller, Julia Münch, Charles Redwood, Arne Hansen, Monica Patten, Thomas Eschenhagen, Giulia Mearini, Lucie Carrier |
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| 520 | |a Gene therapy is a promising option for severe forms of genetic diseases. We previously provided evidence for the feasibility of trans-splicing, exon skipping, and gene replacement in a mouse model of hypertrophic cardiomyopathy (HCM) carrying a mutation in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C). Here we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from an HCM patient carrying a heterozygous c.1358-1359insC MYBPC3 mutation and from a healthy donor. HCM hiPSC-CMs exhibited ∼50% lower MYBPC3 mRNA and cMyBP-C protein levels than control, no truncated cMyBP-C, larger cell size, and altered gene expression, thus reproducing human HCM features. We evaluated RNA trans-splicing and gene replacement after transducing hiPSC-CMs with adeno-associated virus. trans-splicing with 5′ or 3′ pre-trans-splicing molecules represented ∼1% of total MYBPC3 transcripts in healthy hiPSC-CMs. In contrast, gene replacement with the full-length MYBPC3 cDNA resulted in ∼2.5-fold higher MYBPC3 mRNA levels in HCM and control hiPSC-CMs. This restored the cMyBP-C level to 81% of the control level, suppressed hypertrophy, and partially restored gene expression to control level in HCM cells. This study provides evidence for (1) the feasibility of trans-splicing, although with low efficiency, and (2) efficient gene replacement in hiPSC-CMs with a MYBPC3 mutation. | ||
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