Development of individualized treatment strategies for titin-based dilated cardiomyopathy

基于肌联蛋白的扩张型心肌病个体化治疗策略的制定

• 批准号: 447535517
• 负责人: Professor Dr. Michael Gramlich
• 金额: --
• 依托单位: Klinik für Kardiologie, Angiologie und Internistische Intensivmedizin (Med. Klinik I)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/447535517?language=en
• 关键词: Development; individualized; treatment; strategies; titin

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.

扩张型心肌病（DCM）是一种多因素疾病。巨大肌节蛋白肌联蛋白（TTN）的突变占所有家族性病例的约20%。目前尚无针对肌联蛋白型DCM患者的特异性治疗。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联蛋白特异性治疗方法。反义疗法可应用于跳过突变的肌联蛋白外显子，导致更短但功能完整的肌联蛋白蛋白。该方法抑制了肌联蛋白小鼠模型中心力衰竭的发展，并改善了患者特异性iPS-心肌细胞中的收缩功能和肌节组织。使用广泛的肌联蛋白特异性细胞培养和动物模型，我们现在希望将我们的反义治疗方法扩展到其他肌联蛋白外显子，并通过优化反义寡核苷酸化学来改善心脏可用性。 我们还将评估其他肌联蛋白特异性治疗方法，例如通过用小化合物或siRNA靶向肌联蛋白启动子。