Antisense‐mediated exon skipping: a therapeutic strategy for titin‐based dilated cardiomyopathy
Abstract Frameshift mutations in the TTN gene encoding titin are a major cause for inherited forms of dilated cardiomyopathy (DCM), a heart disease characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. To date, there are no specific treatment options for DCM p...
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-03-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201505047 |
| _version_ | 1827015150949892096 |
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| author | Michael Gramlich Luna Simona Pane Qifeng Zhou Zhifen Chen Marta Murgia Sonja Schötterl Alexander Goedel Katja Metzger Thomas Brade Elvira Parrotta Martin Schaller Brenda Gerull Ludwig Thierfelder Annemieke Aartsma‐Rus Siegfried Labeit John J Atherton Julie McGaughran Richard P Harvey Daniel Sinnecker Matthias Mann Karl‐Ludwig Laugwitz Meinrad Paul Gawaz Alessandra Moretti |
| author_facet | Michael Gramlich Luna Simona Pane Qifeng Zhou Zhifen Chen Marta Murgia Sonja Schötterl Alexander Goedel Katja Metzger Thomas Brade Elvira Parrotta Martin Schaller Brenda Gerull Ludwig Thierfelder Annemieke Aartsma‐Rus Siegfried Labeit John J Atherton Julie McGaughran Richard P Harvey Daniel Sinnecker Matthias Mann Karl‐Ludwig Laugwitz Meinrad Paul Gawaz Alessandra Moretti |
| author_sort | Michael Gramlich |
| collection | DOAJ |
| description | Abstract Frameshift mutations in the TTN gene encoding titin are a major cause for inherited forms of dilated cardiomyopathy (DCM), a heart disease characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. To date, there are no specific treatment options for DCM patients but heart transplantation. Here, we show the beneficial potential of reframing titin transcripts by antisense oligonucleotide (AON)‐mediated exon skipping in human and murine models of DCM carrying a previously identified autosomal‐dominant frameshift mutation in titin exon 326. Correction of TTN reading frame in patient‐specific cardiomyocytes derived from induced pluripotent stem cells rescued defective myofibril assembly and stability and normalized the sarcomeric protein expression. AON treatment in Ttn knock‐in mice improved sarcomere formation and contractile performance in homozygous embryos and prevented the development of the DCM phenotype in heterozygous animals. These results demonstrate that disruption of the titin reading frame due to a truncating DCM mutation can be restored by exon skipping in both patient cardiomyocytes in vitro and mouse heart in vivo, indicating RNA‐based strategies as a potential treatment option for DCM. |
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| issn | 1757-4676 1757-4684 |
| language | English |
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| publishDate | 2015-03-01 |
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| series | EMBO Molecular Medicine |
| spelling | doaj.art-7c654a80f21048ac9a078d405a3d0a792024-10-28T08:59:09ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-03-017556257610.15252/emmm.201505047Antisense‐mediated exon skipping: a therapeutic strategy for titin‐based dilated cardiomyopathyMichael Gramlich0Luna Simona Pane1Qifeng Zhou2Zhifen Chen3Marta Murgia4Sonja Schötterl5Alexander Goedel6Katja Metzger7Thomas Brade8Elvira Parrotta9Martin Schaller10Brenda Gerull11Ludwig Thierfelder12Annemieke Aartsma‐Rus13Siegfried Labeit14John J Atherton15Julie McGaughran16Richard P Harvey17Daniel Sinnecker18Matthias Mann19Karl‐Ludwig Laugwitz20Meinrad Paul Gawaz21Alessandra Moretti22Department of Cardiology and Cardiovascular Diseases, Eberhard Karls UniversityI. Medical Department – Cardiology, Klinikum rechts der Isar – Technische Universität MünchenDepartment of Cardiology and Cardiovascular Diseases, Eberhard Karls UniversityI. Medical Department – Cardiology, Klinikum rechts der Isar – Technische Universität MünchenDepartment of Proteomics and Signal Transduction, Max Planck Institute of BiochemistryDepartment of Cardiology and Cardiovascular Diseases, Eberhard Karls UniversityI. Medical Department – Cardiology, Klinikum rechts der Isar – Technische Universität MünchenDepartment of Cardiology and Cardiovascular Diseases, Eberhard Karls UniversityI. Medical Department – Cardiology, Klinikum rechts der Isar – Technische Universität MünchenI. Medical Department – Cardiology, Klinikum rechts der Isar – Technische Universität MünchenDepartment of Dermatology, Eberhard Karls UniversityLibin Cardiovascular Institute of Alberta and University of CalgaryMax Delbrueck Center for Molecular MedicineDepartment of Human Genetics, Leiden University Medical CenterInstitute for Integrative Pathophysiology, Universitätsmedizin MannheimDepartment of Cardiology, Royal Brisbane and Women's Hospital and University of Queensland School of MedicineGenetic Health Queensland, Royal Brisbane and Women's HospitalVictor Chang Cardiac Research InstituteI. Medical Department – Cardiology, Klinikum rechts der Isar – Technische Universität MünchenDepartment of Proteomics and Signal Transduction, Max Planck Institute of BiochemistryI. Medical Department – Cardiology, Klinikum rechts der Isar – Technische Universität MünchenDepartment of Cardiology and Cardiovascular Diseases, Eberhard Karls UniversityI. Medical Department – Cardiology, Klinikum rechts der Isar – Technische Universität MünchenAbstract Frameshift mutations in the TTN gene encoding titin are a major cause for inherited forms of dilated cardiomyopathy (DCM), a heart disease characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. To date, there are no specific treatment options for DCM patients but heart transplantation. Here, we show the beneficial potential of reframing titin transcripts by antisense oligonucleotide (AON)‐mediated exon skipping in human and murine models of DCM carrying a previously identified autosomal‐dominant frameshift mutation in titin exon 326. Correction of TTN reading frame in patient‐specific cardiomyocytes derived from induced pluripotent stem cells rescued defective myofibril assembly and stability and normalized the sarcomeric protein expression. AON treatment in Ttn knock‐in mice improved sarcomere formation and contractile performance in homozygous embryos and prevented the development of the DCM phenotype in heterozygous animals. These results demonstrate that disruption of the titin reading frame due to a truncating DCM mutation can be restored by exon skipping in both patient cardiomyocytes in vitro and mouse heart in vivo, indicating RNA‐based strategies as a potential treatment option for DCM.https://doi.org/10.15252/emmm.201505047dilated cardiomyopathyexon skippinginduced pluripotent stem cellstitin |
| spellingShingle | Michael Gramlich Luna Simona Pane Qifeng Zhou Zhifen Chen Marta Murgia Sonja Schötterl Alexander Goedel Katja Metzger Thomas Brade Elvira Parrotta Martin Schaller Brenda Gerull Ludwig Thierfelder Annemieke Aartsma‐Rus Siegfried Labeit John J Atherton Julie McGaughran Richard P Harvey Daniel Sinnecker Matthias Mann Karl‐Ludwig Laugwitz Meinrad Paul Gawaz Alessandra Moretti Antisense‐mediated exon skipping: a therapeutic strategy for titin‐based dilated cardiomyopathy EMBO Molecular Medicine dilated cardiomyopathy exon skipping induced pluripotent stem cells titin |
| title | Antisense‐mediated exon skipping: a therapeutic strategy for titin‐based dilated cardiomyopathy |
| title_full | Antisense‐mediated exon skipping: a therapeutic strategy for titin‐based dilated cardiomyopathy |
| title_fullStr | Antisense‐mediated exon skipping: a therapeutic strategy for titin‐based dilated cardiomyopathy |
| title_full_unstemmed | Antisense‐mediated exon skipping: a therapeutic strategy for titin‐based dilated cardiomyopathy |
| title_short | Antisense‐mediated exon skipping: a therapeutic strategy for titin‐based dilated cardiomyopathy |
| title_sort | antisense mediated exon skipping a therapeutic strategy for titin based dilated cardiomyopathy |
| topic | dilated cardiomyopathy exon skipping induced pluripotent stem cells titin |
| url | https://doi.org/10.15252/emmm.201505047 |
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