DECISION

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.

Cardiovascular disease (CVD) and dementia are closely intertwined, often resulting in cognitive impairment among individuals with cardiovascular or cerebrovascular conditions. Approximately one-third of dementia cases are linked to vascular injury, emphasizing that vascular cognitive impairment (VCI) is a preventable aspect of cognitive decline. The Focus The Heart-Brain Connection Crossroads (HBCx) consortium investigates hemodynamic alterations as reversible contributors to VCI, seeking to enhance our understanding of the connection between cardiovascular health and cognitive function. The Research HBCx builds upon the foundation laid by HBC1 (CVON 2012-06), which established a national network dedicated to studying, diagnosing, and treating VCI. Clinical investigations within HBC1, focusing on patients with chronic heart failure (CHF), carotid occlusive disease (COD), and clinically evident VCI, emphasized the role of hemodynamics along the heart-brain axis in VCI. These findings underscored significant associations between heart-brain connections and VCI. The HBCx program, launched in 2019, takes a comprehensive approach by investigating hemodynamics in key cardiac conditions such as atrial fibrillation and heart failure, while also exploring vascular factors and their interplay with amyloid pathology. Moreover, HBCx considers modulating factors like age and sex. The program aims to improve early detection, identify treatable targets, and integrate the Heart-Brain Connection approach into routine care. Ultimately, the long-term vision of HBCx is to reduce VCI prevalence among CVD patients through enhanced understanding and innovative treatment strategies. Origin This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation.