Development and validation of a repurposing platform for drug discovery to treat cardiomyopathy.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. A subset of CVDs that remain particularly challenging to treat are cardiomyopathies (CMs) or ‘diseases of the heart muscle’. CMs are heterogeneous in origin and phenotype and mostly caused by an ever increasing number of gene mutations. The long-term benefits of current generalised pharmacological approaches are uncertain and these drugs only relieve symptoms instead of modifying disease development or outcome. Hence, there is a critical need for (personalised) drugs that target the mechanisms responsible for specific types of CM. One major challenge, especially for diseases like CM that likely require a specific drug for each disease subtype, is the increasing cost and duration of the classical path of new drug discovery and development. Drug repurposing, a process in which the cost and duration of the path to drug approval can be significantly reduced by redirecting existing drugs with a documented safety profile and mode-of-action to another disease, is an appealing way to address this challenge. This project is aimed at developing a drug repurposing platform to discover drugs with activity against different CM subtypes. This innovative platform is based on a complement of zebrafish CM models from which we will first derive CM-type specific gene/pathway passports for which we will find matching compounds from a repurposing library. Found hits will be validated in mouse and human CM models.