OUTREACH

Pulmonary Hypertension (PH), particularly Pulmonary Arterial Hypertension (PAH), presents a fatal complication in chronic diseases, affecting 1 in 50,000 individuals, predominantly at a young age and more often in females. The underlying genetic link involves mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, disrupting BMP signaling. The PHAEDRA-IMPACT consortium aims to understand PH and PAH. The Research The research focuses on understanding PAH through the transforming growth factor-β (TGFβ) signaling pathway, particularly influenced by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, prevalent in heritable and some non-hereditary PAH cases. The PHAEDRA initiative identified compounds that modulate the TGFβ/BMP balance, showing efficacy in restoring endothelial function and reversing pulmonary vascular remodeling in preclinical models, though not curing PAH, making early detection crucial. PHAEDRA has identified biomarkers for timely diagnosis and personalized treatment. PHAEDRA-IMPACT will enhance early detection using non-invasive risk assessments, imaging, and biomarker profiling to detect pre-capillary PH. Precision medicine will guide tailored therapies based on advanced imaging and biomarker analyses, addressing disease progression variability among predisposed individuals. Additionally, patient-derived induced pluripotent stem (iPS) cells will be used in 3D culture models of lung and heart tissues to uncover PAH mechanisms and identify therapeutic targets. This comprehensive approach aims to advance our understanding of PAH pathogenesis, accelerate drug development, and enable personalized treatment and preventive strategies for individuals at risk or affected by PH. Origin This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation.

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.