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Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes
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| Veröffentlicht in: | Molecular Therapy / Nucleic Acids 7(2017), Seite 475-486 |
|---|---|
| Personen und Körperschaften: | , |
| Titel: | Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes/ 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 |
| Format: | E-Book-Kapitel |
| Sprache: | Englisch |
| veröffentlicht: |
16 June 2017
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| Gesamtaufnahme: |
: Molecular Therapy / Nucleic Acids, 7(2017), Seite 475-486
, volume:7 |
| Schlagwörter: | |
| Quelle: | Verbunddaten SWB Lizenzfreie Online-Ressourcen |
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| 245 | 1 | 0 | |a Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes |c 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. | ||
| 650 | 4 | |a -splicing | |
| 650 | 4 | |a gene replacement | |
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| 650 | 4 | |a hypertrophic cardiomyopathy | |
| 700 | 1 | |a Müller, Oliver J. |d 1971- |e VerfasserIn |0 (DE-588)121693449 |0 (DE-627)705619621 |0 (DE-576)292833504 |4 aut | |
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| contents | 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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| spelling | Prondzynski, Maksymilian VerfasserIn (DE-588)1155738578 (DE-627)1017943435 (DE-576)50182118X aut, Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes 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, 16 June 2017, 12, Text txt rdacontent, Computermedien c rdamedia, Online-Ressource cr rdacarrier, Gesehen am 09.04.2018, 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., -splicing, gene replacement, human induced pluripotent stem cell-derived cardiomyocytes, hypertrophic cardiomyopathy, Müller, Oliver J. 1971- VerfasserIn (DE-588)121693449 (DE-627)705619621 (DE-576)292833504 aut, Enthalten in Molecular Therapy / Nucleic Acids New York, NY : Nature Publ. Group, 2012 7(2017), Seite 475-486 Online-Ressource (DE-627)718632702 (DE-600)2662631-7 (DE-576)365782785 2162-2531 nnns, volume:7 year:2017 pages:475-486 extent:12, http://dx.doi.org/10.1016/j.omtn.2017.05.008 Verlag Resolving-System kostenfrei Volltext, http://www.sciencedirect.com/science/article/pii/S2162253117301798 Verlag kostenfrei Volltext, http://dx.doi.org/10.1016/j.omtn.2017.05.008 LFER, LFER 2018-05-17T00:00:00Z |
| spellingShingle | Prondzynski, Maksymilian, Müller, Oliver J., 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 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., -splicing, gene replacement, human induced pluripotent stem cell-derived cardiomyocytes, hypertrophic cardiomyopathy |
| swb_id_str | 501801855 |
| title | Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes |
| title_auth | Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes |
| title_full | Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes 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 |
| title_fullStr | Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes 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 |
| title_full_unstemmed | Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes 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 |
| title_in_hierarchy | Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes / 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, |
| title_short | Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-Derived cardiomyocytes |
| title_sort | evaluation of mybpc3 trans splicing and gene replacement as therapeutic options in human ipsc derived cardiomyocytes |
| topic | -splicing, gene replacement, human induced pluripotent stem cell-derived cardiomyocytes, hypertrophic cardiomyopathy |
| topic_facet | -splicing, gene replacement, human induced pluripotent stem cell-derived cardiomyocytes, hypertrophic cardiomyopathy |
| url | http://dx.doi.org/10.1016/j.omtn.2017.05.008, http://www.sciencedirect.com/science/article/pii/S2162253117301798 |