Title: Towards Personalised Medicine in the Clinic: Novel RNA Therapies aimed at heritable forms of treatment-resistant Heart Failure.
The former CVON-ARENA programme (2012-2017) contributed to the discovery and elucidation of prominent mechanisms by which different cardiac RNA species (microRNAs, lncRNAs and circular RNAs) are involved in development and progression of diverse forms of heart failure (HF). Importantly, ARENA established a national framework that successfully connected to international partners and new EU research projects.
The DCVA-ARENA-PRIME programme (2018-2023) shifts its focus towards forms of HF that are resistant to current treatment forms. In previous decades, generally applied therapies substantially improved survival of patients with HF. However, in a minority of patients, these treatments fail to halt the progression of the disease. This particularly concerns younger patients with forms of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). DCVA-ARENA-PRIME focuses on the development of novel gene therapies targeted at individual disease mechanism of DCM caused by mutations in the RBM20 and LMNA genes as well as ACM caused by mutations in the DSGL2 and PKP2 genes.
The DCVA-ARENA-PRIME investigators capitalize on the knowledge gained from foregoing and complementary programmes on cardiac gene therapies (e.g., inhibitory RNAs such as allele-specific short hairpin RNAs, antimiRs, etc.) and gene editing technologies (e.g., base- and prime editing) to find novel cures for DCM and ACM. This highly translational work are complemented with cutting-edge research on adeno-associated viral (AAV) vectors to improve cardiac delivery of the gene therapies. They will also connect the national wealth of heart tissue collections to novel high-end sequencing- technologies like single-cell sequencing to further explore disease mechanisms. Ultimately, they aim to bring forward a novel therapeutic approach that will be tested in a first-in-human clinical trial with patients carrying the LMNA disease, and reach preclinical proof-of-concept of DSGL2- and PKP2- ACM directed therapies on their path towards clinical reality.
First, the participatory approach proposed embedded the DCVA-ARENA-PRIME programme ensures close involvement and most likely collaborative actions with stakeholders and (end-) users. Within this programme users are not only closely involved in the design of the studies (co-creation), they will also be involved in the implementation of the co-created studies and deliverables.
As of the start of the DCVA-ARENA-PRIME programme, a (end-) user committee has been established. This committee meets once per year in conjunction with the programme’s research meetings and advises the investigators about the course of the programme and what actions need to be taken in order to maximise the probability that the (end-) users will be able to utilize and/or benefit from the results. This committee addresses any comments, remarks, questions and advice they may have, solicited or otherwise.
Members of the DCVA-ARENA-PRIME user committee include cardiomyopathy patients and patient relatives, clinicians (e.g., cardiologists), representatives of complementary research programmes (e.g., RegMedXB, H2020-TRAIN-HEART), and industry representatives from biotech and pharma companies and venture capitalists.
One of DCVA key missions is to attract and connect new talents from different disciplines and provide opportunities and programmes for developing their careers. In the research actions of the DCVA-ARENA-PRIME programme >20 young investigators are involved. They are a given hands-on training to acquire innovative skills, and are exposed to a highly collaborative and translational environment. This will help them grow toward independent and creative researchers.
To further support this career development, five fellowship awards of 50.000€ have been granted the past three years to junior postdoctoral researchers in the laboratories of the Hubrecht Institute, University Medical Center Utrecht, Amsterdam UMC (location VUmc and AMC) and Maastricht University.