Towards targeted therapies for phospholamban cardiomyopathy
In this PhD thesis, we investigated the cardiomyopathy (heart muscle disorder) that results from the p.Arg14del (R14del) mutation of the phospholamban (PLN) gene. This is a common genetic deviation, especially in the Netherlands, and mutation carriers have an increased risk of developing heart failure. Little is known about how this mutation leads to cardiomyopathy, and there is no effective cure other than heart transplantation. Therefore, we aimed to generate a novel mouse model to study the disease pathophysiology and screen therapeutic options. First, we validated that PLN-R14del mice develop heart failure with similar disease characteristics as has been observed in human patients. We examined the molecular changes that underlie the disease in great detail and in association with disease progression. We concluded that PLN protein aggregation in the cardiomyocytes of PLN-R14del mice was (one of) the first hallmark(s) of the disease, and therefore may play a causal role. Finally, we tested several therapeutic therapies in this new mouse model. Standard heart failure medication did not improve the disease, and therefore we tested experimental treatments that are not (yet) commercially available. Reducing the amount of PLN and PLN aggregation in the heart using an RNA therapy approach was found to be successful. Further research is required to establish whether (chronic) use of this treatment is also safe and effective in human patients, but these first results are very promising.