TY - JOUR

T1 - Antisense-mediated exon skipping

T2 - a therapeutic strategy for titin-based dilated cardiomyopathy

AU - Gramlich, Michael

AU - Pane, Luna Simona

AU - Zhou, Qifeng

AU - Chen, Zhifen

AU - Murgia, Marta

AU - Schötterl, Sonja

AU - Goedel, Alexander

AU - Metzger, Katja

AU - Brade, Thomas

AU - Parrotta, Elvira

AU - Schaller, Martin

AU - Gerull, Brenda

AU - Thierfelder, Ludwig

AU - Aartsma-Rus, Annemieke

AU - Labeit, Siegfried

AU - Atherton, John J

AU - McGaughran, Julie

AU - Harvey, Richard P

AU - Sinnecker, Daniel

AU - Mann, Matthias

AU - Laugwitz, Karl-Ludwig

AU - Gawaz, Meinrad Paul

AU - Moretti, Alessandra

N1 - © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2015/3/9

Y1 - 2015/3/9

N2 - 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.

AB - 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.

U2 - 10.15252/emmm.201505047

DO - 10.15252/emmm.201505047

M3 - Journal article

C2 - 25759365

VL - 7

SP - 562

EP - 576

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

IS - 5

ER -