Cardiovascular Moonshot (RegMed XB)

The successful treatment of congenital heart disease (ConHD) has greatly increased the survival of children with this condition. Many of these defects require surgical or catheter interventions immediately after birth. However, complete restoration of the defect is often unachievable, a high risk of developing heart failure, arrhythmias, sudden cardiac death or blood vessel dilatation or stenosis relatively early in life. Currently, there is a lack of personalized risk predictors and optimal clinical decision tools, highlighting an unmet need to develop new effective strategies for treating and preventing ventricular failure, arrhythmias, and large vessel diseases. The Focus The OUTREACH consortium focuses on specific types of congenital heart diseases (ConHD) related to outflow tract defects, such as transposition of the great arteries, congenital aortic stenosis, and tetralogy of Fallot, which collectively account for over half of all ConHD cases. The goal of OUTREACH is to reduce the risk of mortality and morbidity and improve the quality of life for these patients (both children and adults) by improving follow-up practices based on outcomes, implementing personalized risk assessment tools, and advancing therapeutic strategies. The Research The OUTREACH consortium integrates expertise in preclinical research, developmental biology, disease modeling, and clinical research from academic centers specializing in pediatric and adult congenital cardiology and surgery. Its objectives are: identifying better parameters for risk assessment and early detection of heart failure or ventricular arrhythmias in ConHD patients with outflow tract defects. Exploring efficient treatments to enhance adaptation and prevent heart failure and vascular damage in at-risk ConHD patients. This consortium conducts extensive research involving a large cohort of ConHD patients to unravel the underlying causes and mechanisms of cardiac adaptations following surgical interventions. It investigates the molecular mechanisms responsible for outflow tract defects and evaluates whether stimulating heart regeneration in ConHD models can mitigate adverse remodeling and heart failure. Additionally, the consortium explores new non-invasive imaging techniques and blood-derived biomarkers to develop innovative risk analysis tools for clinical decision-making. In OUTREACH a nationwide registry is created for all patients (children and adults) with ConHD in the Netherlands by harmonizing existing registries KinCor and ConCor. This is an important step towards optimizing the quality of care for the ConHD population and fostering scientific research on ConHD. Origin The Dutch Heart Foundation and Stichting Hartekind, who collaborate within the Dutch CardioVascular Alliance, initiated an invitational grant to start and fund large-scale research aimed at earlier detection and better treatment of the consequences of congenital heart defects.

In preceding decades, conventional therapies have notably enhanced the survival rates of heart failure (HF) patients. However, a subset of individuals, particularly younger patients afflicted with dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM), still confront disease progression despite these treatments. This underscores the necessity for innovative approaches. The ARENA-PRIME initiative aims to address this gap by focusing on the development of novel gene therapies tailored to the specific disease mechanisms underlying DCM, attributed to mutations in the RBM20 and LMNA genes, as well as ACM, and associated with mutations in the DSGL2 and PKP2 genes. The goal is to progress towards first-in-human clinical trials, particularly focusing on LMNA disease, and to establish preclinical proof-of-concept for ACM therapies targeting DSGL2 and PKP2. The Research The ARENA-PRIME researchers utilize insights from previous 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 develop novel treatments for dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). This effort is supplemented by advanced research on adeno-associated viral vectors and the integration of heart tissue collections with cutting-edge sequencing technologies (like single-cell sequencing) to further explore disease mechanisms. At the beginning of the ARENA-PRIME programme, a (end-) user committee has been established, making sure that (end-)users are  closely involved in the design of the studies and the implementation of the co-created studies and deliverables. This committee meets annually alongside the program's research meetings to provide guidance to investigators on optimizing the program's outcomes for (end-) users. It addresses all feedback, inquiries, and recommendations, whether requested or spontaneous. 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. The members of the ARENA-PRIME user committee include cardiomyopathy patients and their relatives, clinicians (e.g. cardiologists), representatives from related research programs (e.g., RegMedXB, H2020-TRAIN-HEART), and industry stakeholders including biotech and pharma company representatives and venture capitalists. Supporting Young Investigators The programme prioritizes attracting and nurturing young talent, providing hands-on training and fellowship awards to facilitate their career development. Over 20 young investigators participate, benefiting from exposure to collaborative research environments. 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. Origin The former CVON-ARENA programme (2012-2017) advanced understanding of cardiac RNA species in heart failure (microRNAs, lncRNAs and circular RNAs). The CVON-ARENA programme (2012-2017) advanced understanding of cardiac RNA species, such as microRNAs, lncRNAs, and circular RNAs, in various forms of heart failure (HF). This subsequent ARENA-PRIME programme (2018-2023), funded by the Dutch Heart Foundation, targets treatment-resistant HF forms, particularly in younger patients with dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). In 2023 ARIME-PRIME received a matching grant from the Dutch Heart Foundation to work on their research together with a private partners, so that they can achieve their ambitions and objectives more quickly.