WP4 will develop ncRNA-based therapeutic strategies for cardiac disease in small and large animal models with chronological and premature ageing (based on WP1 and WP2 results). We aim to use the diagnostic ncRNA panel from WP3 to study its potential in monitoring therapeutic efficacy (companion diagnostic approach).
Both previously identified ageing-related targets (Le. miR-22, miR-708, H19) as well as new ncRNA pathways identified in WP1 & 2 will be investigated. We will choose the 5 most promising age-related ncRNA-based targets from mouse HF models, one of which will be further tested in a large animal (pig) after assessing indicative toxicological safety.
Initially, the top 5 most promising ncRNAs will be investigated in normal and premature cellular and mouse models of age-associated cardiac disease (see WP1 for mouse models). Additionally, mice will be challenged with cardiovascular risk factors (diabetes, hypertension, hyperlipidemia) to closely mimic clinical reality. ncRNA therapy will consist of either chemically modified and stabilized antisense oligonucleotides for ncRNAs silencing or the delivery of ncRNAs using adeno-associated virus-9 (AAV9) vector-based delivery strategies.