Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy.
Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy.
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DOI：
10.15252/emmm.201505047
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发表时间：
2015-05
影响因子：
11.1
通讯作者：
Moretti A
中科院分区：
文献类型：
--
作者：
Gramlich M;Pane LS;Zhou Q;Chen Z;Murgia M;Schötterl S;Goedel A;Metzger K;Brade T;Parrotta E;Schaller M;Gerull B;Thierfelder L;Aartsma-Rus A;Labeit S;Atherton JJ;McGaughran J;Harvey RP;Sinnecker D;Mann M;Laugwitz KL;Gawaz MP;Moretti A
编码Titin的TTN基因移码突变是遗传性扩张型心肌病(DCM)的主要原因，DCM是一种以心室扩张、收缩功能障碍和进行性心力衰竭为特征的心脏病。到目前为止，除了心脏移植，还没有针对扩张型心肌病患者的特定治疗选择。在这里，我们展示了通过反义寡核苷酸(AON)介导的外显子跳过在人类和小鼠DCM模型中重构Titin转录物的有益潜力，该模型携带先前发现的Titin外显子326的常染色体显性移码突变。纠正来自诱导多能干细胞的患者特异性心肌细胞中的TTN读框，挽救了肌原纤维组装和稳定性缺陷，并使肌节蛋白表达正常化。对TTN基因敲入小鼠的AON治疗改善了纯合子胚胎中肌节的形成和收缩性能，并阻止了杂合子动物中DCM表型的发展。这些结果表明，在体外患者心肌细胞和体内小鼠心脏中，由于截短的DCM突变而导致的Titin阅读框架的破坏无法通过跳过外显子来恢复，这表明基于RNA的策略是一种潜在的DCM治疗选择。
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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DOI：
10.1038/mtna.2012.30
发表时间：
2012-08-14
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
--
影响因子：
158.5
作者：
Goemans, Nathalie M.;Tulinius, Mar;van Deutekom, Judith C.
通讯作者：
van Deutekom, Judith C.
影响因子：
3.5
作者：
Heemskerk, Hans A.;de Winter, Christa L.;Aartsma-Rus, Annemieke
通讯作者：
Aartsma-Rus, Annemieke
影响因子：
64.5
作者：
GALLI, G;HOFSTETTER, H;BIRNSTIEL, ML
通讯作者：
BIRNSTIEL, ML
影响因子：
11.1
作者：
Gedicke-Hornung, Christina;Behrens-Gawlik, Verena;Reischmann, Silke;Geertz, Birgit;Stimpel, Doreen;Weinberger, Florian;Schlossarek, Saskia;Precigout, Guillaume;Braren, Ingke;Eschenhagen, Thomas;Mearini, Giulia;Lorain, Stephanie;Voit, Thomas;Dreyfus, Patrick A.;Garcia, Luis;Carrier, Lucie
通讯作者：
Carrier, Lucie