Development of individualized treatment strategies for titin-based dilated cardiomyopathy

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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.