RNA - Genetherapys
Spoke 4 - Metabolic and Cardiovascular Diseases


The activities of Spoke 4 are divided into three Work Packages (WPs):
WP 4.1 addresses MUSCLE ATROPHY AND AGING. A disproportionate number of people who reach old age (≈80% of people aged ≥80 years) suffer from cardiovascular and metabolic diseases, cellular and cognitive decline, cancer, sarcopenia, and frailty. By using sh/siRNAs and miRNAs the participating groups have identified a subset of targets that, when inhibited in mouse muscles, result in recovery of mass, force, and mitochondrial function/metabolism in different catabolic conditions such as cancer, immobilization, loss of innervation, diabetes/obesity, and aging. The work will aim at developing effective RNA-based drugs from these fundamental studies.
WP 4.2 addresses OBESITY, METABOLIC SYNDROME, AND DIABETES MELLITUS and their associated metabolic abnormalities and end-organ complications. Adipose tissue remodeling and inflammation are major drivers of obesity-associated insulin resistance and cardiovascular disease. Tackling the dysfunctional adipose tissue will avoid the progression towards the complications of metabolic diseases. In addition, the participating groups have identified several critical molecules in pathogenesis (e.g. Oncostatin M, p66Shc, and Aldosterone Synthase) in type 2 diabetes and in arterial hypertension (crucial components of the metabolic syndrome), which will be targeted with novel RNA-based approaches.

WP 4.3, addresses CARDIOMYOPATHIES. Myocardial diseases include several different pathologies unchained either by intrinsic, but often inherited, defects of the cardiomyocyte, the contractile cellular unit of the myocardium, or by extrinsic noxae, as is the case of myocardial infarction due to coronary atherosclerosis or myocardial fibrosis following uncontrolled high blood pressure. In all cases, myocardial tissue undergoes a profound remodeling, during which the contractile tissue area is decreased and substituted by fibrotic, non-functional tissue, usually after tissue inflammation. The progress in DNA sequencing technology has allowed for the identification of new RNA molecules, which play a critical role in many aspects of cell biology or the study of myocardial cellularity at the single-cell level. Similarly, advances in genomic reprogramming have allowed for the generation of human disease models “in a dish” through the manipulation of patient-specific induced pluripotent stem cells. WP 4.3 aims at exploiting RNA and gene therapy approaches for curing myocardial diseases as well as using cellular reprogramming for establishing models of myocardial disease or for cardiac cell replacement therapy.

Spoke 4


The Spoke 4 coordinator center aims to create a state-of-the-art automated platform for the general propagation and screening of cell lines, spheroids, and organoids. This platform serves as a core facility for the screening of RNA-based drugs with multiple assays using different readouts, including absorbance, fluorescence, luminescence, and imaging. A liquid handler, incubators, plate washer, dispensers, and a multimode plate reader with basic imaging capabilities are included in the platform. High-content microscopy is performed in a separate, nearby facility. Typically, the platform allows the full automation of cell-based assays in 96 and 384 multi-well plates.


Ongoing collaborations are actively underway with both horizontal and vertical spokes. Interactions are currently established or in the planning stages with the following spokes:

Spoke 5 to obtain a better therapeutic protocol and expand therapeutic targets

Spoke 6 for the design of an efficient RNA-based therapy

Spoke 7 for the development of a novel in silico antisense oligonucleotides design

Spoke 8 for the development of smart delivery platforms to target the tissues of interest of the spoke

Spoke 9 for the testing reporter systems for in vitro and in vivo testing RNA delivery and translation efficiency by novel delivery sensors;

Spoke 10 for the preclinical validation of the RNA-based therapies.