Development of individualized treatment strategies for titin-based dilated cardiomyopathy

扩张型心肌病(DCM)是一种多因素疾病。巨型肌节蛋白Titin(TTN)的突变约占所有家族性病例的20%。目前还没有针对基于肌钙蛋白的扩张型心肌病患者的特定治疗方法。治疗选择主要集中在心力衰竭的对症治疗上。我们最近开发了一种使用反义寡核苷酸的肌动蛋白特异性治疗方法。反义治疗可用于跳过突变的Titin外显子，导致较短但功能完整的Titin蛋白。这种方法抑制了Titin小鼠模型心力衰竭的发展，并改善了患者特异性iPS心肌细胞的收缩功能和肌节组织。现在，我们希望利用广泛的Titin特异性细胞培养和动物模型，将我们的反义治疗方法扩展到其他Titin外显子，并通过优化反义寡核苷酸化学来提高心脏利用率。我们还将评估其他针对Titin的治疗方法，例如通过用小化合物或siRNA靶向Titin启动子。

Dilated cardiomyopathy (DCM) is a multifactorial disease. Mutations in the giant sarcomeric protein titin (TTN) account for approximately 20% of all familial cases. A specific therapy for patients with titin-based DCM is currently not available. Therapeutic options mainly focus on symptomatic treatment of heart failure.We have recently developed a titin-specific therapeutic approach using antisense oligonucleotides. Antisense therapy can be applied to skip a mutated titin exon, leading to a shorter, but functionally intact titin protein. This approach inhibited the development of heart failure in a titin mouse model and improved contractile function and sarcomeric organization in patient-specific iPS- cardiomyocytes.Using a broad spectrum of titin-specific cell culture and animal models, we now would like to extend our antisense- therapy approach to other titin exons and improve cardiac availability by optimizing antisense oligonucleotide chemistry. We will also evaluate other titin-specific therapeutic approaches, e.g. by targeting the titin promoter with small compounds or siRNA.