Cardiovascular Moonshot (RegMed XB)

2018

Heart failure is a global public health issue with a largely equal distribution between men and women. For patients with end-stage heart failure limited treatment options are available. The Cardiovascular Moonshot of RegMed-XB (CMRM-XB) is a comprehensive program based on the concept of developing personalized cardiac regenerative therapies tailored to individual patients. The researchers aim to enhance the body's inherent regenerative capacity, such as improving contractility and perfusion of the heart muscle, repairing or replacing coronary arteries and heart valves. Importantly, researchers will gain insights into optimizing heart treatment and potentially preventing certain cardiovascular diseases in patients.

The Research
The research is focused on the creation of a(n) (additional) solution(s) for patients by regenerating the human heart inside (in-situ) or outside of the body (ex-situ). Repair of the heart in a cardiac perfusion bioreactor (ex-situ) offers unique opportunities, including the possibility to apply treatments without off-target effects to distant organs or wash-out of therapeutics. Initially, this could be an option to restore donor hearts for transplant recipients. After restoring the heart, it will be re-implanted. This strategy also facilitates exploration of gene therapy for hereditary diseases. Along this process, the researchers learn how to treat the heart better and eventually also aim to deduce how to treat the heart inside a patient.

The Cardiovascular Moonshot of RegMed XB is the most recent addition to the Moonshot initiatives. To date, it has completed a hypothermic pilot study that has enhanced researchers' expertise in perfusion models. Currently, this model is undergoing further refinement for optimal heart preservation. Additionally, ongoing histopathological analysis of heart valves aims to elucidate how these valves remodel in response to altered fluid dynamics within the ex vivo heart platform.

The cardiovascular Moonshot consists of a multidisciplinary team of transplant surgeons (Utrecht), cardiologists (Utrecht, Maastricht), engineers (Eindhoven) and biologists (Leiden) with the support and input of key stakeholders including patients and companies.

The origin

RegMed XB is a virtual institute that currently comprises Dutch and Belgian public (universities and governments) and private (health foundations and companies) partners that work together to develop regenerative medicine solutions. Regenerative medicine aims to restore degenerated, diseased, or damaged tissues and organs, thereby increasing vital functioning and reducing the cost of healthcare. RegMed XB collaborates on ambitious projects in the field of regenerative medicine. Initially, five health foundations have joined the TKI-program by Health~Holland to define the research objectives and co-govern the projects. Numerous companies have joined and the regional governments support both the research and its valorisation.

The cardiovascular Moonshot recently received follow-up funding from the Dutch Heart Foundation through the Open PSS program, which the Dutch Heart Foundation receives from Health~Holland. In addition, companies involved are also making a financial contribution; these are Coagulation Profile and Axion Biosystems.

Contact person:

Prof. Dr. P. Doevendans (Pieter)

p.doevendans@umcutrecht.nl

Principal investigators

Prof. Dr. P. Doevendans (Pieter)

p.doevendans@umcutrecht.nl

Prof. Dr. C.V.C. Bouten (Carlijn)

c.v.c.bouten@tue.nl

Prof. Dr. M. Goumans (Marie-José)

m.j.goumans@lumc.nl

Dr. B.M.E. Mees (Barend)

barend.mees@mumc.nl

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Cardiomyopathies, caused by genetic mutations affecting cardiac muscle components, pose significant economic and societal burdens due to their hereditary nature and early onset. Despite known genetic defects, predicting disease progression remains challenging due to extreme clinical variability. Recent research indicates that cardiomyopathy mutations induce metabolic stress, exacerbated by factors like obesity, which can accelerate disease progression. The Double Dose hypothesis suggests that targeting metabolic stress may offer preventive or curative strategies for these conditions.
The Focus
The Double Dose Consortium aims to understand how cardiomyopathy-causing mutations lead to structural changes in cardiomyocytes. This interdisciplinary effort combines experts in preclinical research, clinical genetics, health technology assessment, and clinical care focused on cardiomyopathy in both children and adults.
The Research
The consortium combines experts in preclinical research, clinical genetics, health technology assessment and clinical researchers with a strong clinical focus on cardiomyopathy in children and adults. These experts investigate how obesity and muscle adiposity contribute to vascular and cardiac muscle dysfunction in mutation carriers through the analysis of clinical data, patient samples, and experimental models. They will also study the mechanisms underlying ultrastructural changes in cardiomyocytes caused by these mutations, leading to impaired metabolism, contraction, relaxation defects, and disrupted cellular communication within the heart.
Utilizing extensive patient cohorts and ongoing studies, the consortium aims to optimize care for cardiomyopathy patients by assessing the cost-effectiveness of diagnostics and clinical interventions. They plan to translate findings on metabolic alterations into clinical trials targeting treatments that reduce metabolic stress. The Double Dose program will establish biobanks containing serum, tissue, and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to provide mechanistic insights into cardiomyopathy pathophysiology and improve diagnosis and care.
Origin
This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation, together with Stichting Hartedroom. The consortium is a continuation of the Dosis consortium, in which the interaction between mutation and external factors was investigated. They found that cardiomyopathy-mutations induce metabolic stress and that secondary metabolic stress, such as obesity accelerates disease progression.
 

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Phaedra-impact

2018

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.

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