Open AccessAntisense‐mediated exon skipping: a therapeutic strategy for titin‐based dilated cardiomyopathy
Author(s) -
Gramlich Michael,
Pane Luna Simona,
Zhou Qifeng,
Chen Zhifen,
Murgia Marta,
Schötterl Sonja,
Goedel Alexander,
Metzger Katja,
Brade Thomas,
Parrotta Elvira,
Schaller Martin,
Gerull Brenda,
Thierfelder Ludwig,
AartsmaRus Annemieke,
Labeit Siegfried,
Atherton John J,
McGaughran Julie,
Harvey Richard P,
Sinnecker Daniel,
Mann Matthias,
Laugwitz KarlLudwig,
Gawaz Meinrad Paul,
Moretti Alessandra
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201505047
Subject(s) - titin , exon skipping , frameshift mutation , exon , sarcomere , dilated cardiomyopathy , biology , mutation , cardiomyopathy , obscurin , microbiology and biotechnology , heart failure , medicine , cancer research , genetics , alternative splicing , myocyte , gene
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 .