March 2015

Roughly 25 percent of all dilated cardiomyopathies (DCM) are attributable to mutations in the gene encoding the muscle protein titin. In those cases, the largest protein in the human body is truncated because protein synthesis breaks off at the faulty site on the gene. The group of authors led by Karl Laugwitz and Alessandra Moretti from the DZHK partner site Munich examined whether such genetic defects can be treated with the exon skipping method, as already applied in studies of Duchenne muscular dystrophy (DMD). In exon skipping, the faulty parts of the gene responsible for the disruption of protein synthesis are skipped over. Protein synthesis then continues at one of the subsequent gene segments instead. The investigators were able to show that the disruption of protein synthesis could be bridged by administering a corresponding antisense oligonucleotide. Using this treatment approach, it was possible to prevent the emergence of a DCM phenotype in human cardiomyocytes derived from induced pluripotent stem cells from DCM patients as well as in mice with the disease-causing mutation. This approach now has to be tested in large animal models.

Link to the Paper