The TROPOSplice project, led by researcher William Joyce at the CNIC, has been awarded an ERC Starting Grant, securing 1.5 million euros in funding. The initiative proposes an innovative, evolution-inspired strategy to enhance heart relaxation in patients suffering from hypertrophic cardiomyopathy and heart failure with preserved ejection fraction.
Diastolic dysfunction, which affects the heart's relaxation and filling, is a common condition in cardiac diseases such as hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF). This dysfunction is often caused by excessive sensitivity of cardiac myofilaments to calcium and is associated with altered adrenergic signaling, leading to a reduced heart response to adrenaline.
According to William Joyce, the project aims to develop a new generation of RNA therapies to treat diastolic dysfunction, a condition that prevents the heart from relaxing properly and is present in common heart diseases.
With a planned duration of five years, TROPOSplice seeks to lay the groundwork for a completely novel therapeutic strategy based on antisense oligonucleotides. These will work by modifying the RNA processing of the TNNI3 gene, which encodes cardiac troponin I, a protein essential for regulating the contraction and relaxation of cardiac muscle.
The idea stems from a discovery by Joyce and his collaborators, who identified that small mammals like bats and shrews have evolved a natural mechanism for extremely rapid heart relaxation despite their high heart rates. While this mechanism does not occur naturally in humans or most mammals, it could potentially be induced therapeutically using antisense oligonucleotides to increase myocardial relaxation speed.
TROPOSplice proposes to replicate this mechanism in the human heart through an RNA therapy, following a strategy the researcher summarizes as "from bats to patients."
The strategy, explains Joyce, involves inducing a controlled exon skipping of exon 3 of the TNNI3 gene, which would reduce the sensitivity of cardiac muscle fibers to calcium and promote better heart relaxation. He assures that by acting independently of adrenaline receptors, this strategy would be compatible with widely used therapies such as beta-blockers.
To validate this approach, the project will combine studies in cardiomyocytes derived from human pluripotent stem cells with experimental models of cardiovascular disease. The goal is to optimize the design and delivery of antisense oligonucleotides, evaluate their efficacy on cardiac function, and thoroughly analyze their safety before considering future clinical application.
Joyce believes that TROPOSplice could open a new therapeutic avenue for diseases where current options specifically targeting the correction of heart relaxation impairment are limited. Beyond hypertrophic cardiomyopathy and HFpEF, this strategy might have applications in other pathologies characterized by excessive cardiac muscle sensitivity to calcium.
William Joyce holds a Bachelor's degree in Zoology from the University of Manchester (UK) and a PhD in Biosciences from Aarhus University (Denmark). He initially joined Borja Ibáñez's group at the CNIC in September 2023 and, since June 2024, has been a recipient of a Junior Leader fellowship from the "la Caixa" Foundation.
ERC Starting Grants fund highly innovative projects led by early-stage researchers, aiming to drive transformative ideas at the frontier of knowledge. The TROPOSplice project fully embodies this philosophy by combining evolutionary biology, molecular biology, and translational medicine to develop a new therapeutic concept for some of the most clinically impactful cardiovascular diseases.
