Project 1
SEARCH Trial: Atorvastatin for Arrhythmogenic Cardiomyopathy
Arrhythmogenic cardiomyopathy (ACM) is a genetic heart disease that can lead to severe arrhythmias, heart failure, and sudden cardiac death, particularly in young individuals. Current therapies are mainly symptomatic and do not halt disease progression.
Recent studies have shown that elevated circulating levels of oxidized low-density lipoprotein (oxLDL) are associated with more severe forms of ACM, and that atorvastatin can prevent disease development in preclinical models. To determine whether atorvastatin can also slow disease progression in patients, the SEARCH clinical trial has been launched. SEARCH is a randomized, double-blind, placebo-controlled study involving 102 ACM patients treated for 18 months.
The primary endpoint is the evaluation of changes in right ventricular function. Secondary endpoints include the assessment of arrhythmic burden, ECG parameters, imaging findings, and circulating biomarkers. SEARCH will provide the first clinical evidence on the efficacy of atorvastatin in modifying ACM progression, paving the way for new targeted therapeutic strategies.
Project 2
Advanced Cardiac Organoids for Modeling Heart Disease and Drug Responses
Understanding the mechanisms underlying cardiac diseases requires in vitro models capable of reproducing the complexity of the heart, including the interactions among its different cellular populations and the influence of environmental factors, such as extracellular matrix remodeling and responses to pharmacological treatments.
The development of advanced in vitro systems is a rapidly evolving field of research. To address this need, we have developed an innovative method for generating cardiac organoids—small three-dimensional structures approximately half a millimeter in diameter—that recapitulate both the multicellular composition and the complex architectural organization of cardiac tissue, including chamber-like structures.
This high-throughput and cost-effective platform allows the non-destructive measurement of functional parameters in organoids following pharmacological treatment. Using this model, it is possible to assess drug-induced cardiotoxicity and reproduce key features of genetic cardiomyopathies, whose complexity cannot yet be fully recapitulated by traditional in vitro models or animal models, such as arrhythmogenic cardiomyopathy (ACM).
Project 3
Modeling Duchenne Muscular Dystrophy–Associated Cardiomyopathy Using Patient-Derived iPSCs
Muscular dystrophy (MD) is a genetic disorder caused by mutations in the dystrophin gene. The two main forms are Duchenne Muscular Dystrophy (DMD), characterized by early onset and severe progression, and Becker Muscular Dystrophy (BMD), which typically exhibits a later onset and a more variable clinical course.
Both conditions affect skeletal and cardiac muscle, significantly reducing life expectancy. While therapeutic advances have improved survival, cardiomyopathy has become one of the leading causes of death in these patients.
Identifying the mechanisms responsible for the development and variability of cardiomyopathy in patients with muscular dystrophy is therefore of paramount importance. The aim of this project is to generate induced pluripotent stem cell (iPSC) lines derived from patients with Duchenne muscular dystrophy, in collaboration with the iPSC Facility for Cardiac Modelling and Function, differentiate them into cardiomyocytes, and analyze their cardiac phenotypes.
The in vitro findings will then be correlated with the clinical data of the specific patients from whom the iPSCs were generated. This approach will help elucidate the mechanisms underlying dystrophin-associated cardiomyopathy, with the goal of identifying potential therapeutic targets and, ultimately, predictive biomarkers for disease development and progression.
