DESMOJOINT

Arrhythmogenic cardiomyopathy (ACM) is a rare but serious cardiac disorder characterized by a progressive replacement of the myocardium with fibro-adipose tissue, which predisposes individuals to arrhythmias, heart failure and sudden cardiac death. This inherited condition often results from mutations in genes encoding cardiac desmosome proteins, including desmoplakin (DSP). Individuals with pathogenic variants of DSP exhibit left ventricular involvement, extensive fibrosis, increased arrhythmic risk.

Recently, a new antisense lncRNA, namely DSP-AS1, was identified, which partly overlaps with the DSP gene sequence. Our group demonstrated that this lncRNA exerts an inhibitory effect on the transcription of the DSP gene, leading to a reduction in the expression of the desmoplaskin protein. This discovery suggests a potential therapeutic approach in patients carrying DSP mutations. Using a specific molecule to inhibit DSP-AS1, we aim to rescue the ACM phenotype by restoring DSP expression, obtained from human induced pluripotent stem cells (hiPSCs), carrying mutations causing DSP deficiency.

To achieve this goal, we will collaborate with the Cardiocentro Ticino Institute (Switzerland), our partner in the project, with University of Padua (Italy) and University of Ghent (Belgium), exploiting hiPSC line generated from a patient with a mutation in DSP and its isogenic control.

This joint Italy-Switzerland project will focus on understanding the interaction between lncRNA DSP-AS1 and DSP in different cardiac cell types in this clinically relevant context, using a specific molecule capable of regulating the expression of DSP-AS1.

Finally, as the inhibition of DSP-AS1 represents a new therapeutic approach in ACM, we will explore the use of extracellular vesicles to deliver this molecule can inhibit it in 3D human cell models, such as multicellular micro-tissues and engineered tissues.