Cachexia, the post-illness wasting becomes a study project

Muscles are drastically reduced, along with weight: the body appears more and more “skin and bones” while fatigue increases, becoming chronic. This condition of wasting, which in medicine is called cachexia, is accompanied by many pathologies. Cancer, for example: it is estimated that it affects about 80% of patients with advanced-stage cancer, and often also affects the possibility of receiving the most effective treatments.

But it can also arise in those who have AIDS, rheumatoid arthritis, or heart, kidney or lung problems. There is no cure, and the mechanisms underlying this complex syndrome, which affects multiple organs at the same time, are not well understood.

To discover them, the European Research Council (ERC) is now investing 2.5 million euros: this is the value of the funding - the ERC Advanced Grant - just won by the research group of Marco Sandri , professor of Biomedical Sciences at the University of Padua, for a five-year project dedicated to understanding the biological causes of cachexia.

The research project

The research group coordinated by Sandri has been studying cachexia for a long time. Studies published in the past had led, for example, to the identification of possible genes involved in the onset of this disorder in mice. Now, the soul of the research project funded by Erc Advanced is twofold: on the one hand, the objective is to verify whether the mechanisms identified in animal models are the same ones involved in the onset of the pathology in humans; on the other, Sandri and colleagues will try in parallel to develop molecules capable of counteracting these mechanisms. Not only that, the idea is also to try to understand whether there are differences between men and women, people of different ages and ethnicities, with more or less complex clinical pictures and different types of tumors, in order to aim at the development of possible treatments that are as specific as possible.

"We are at the beginning - explains Sandri -. It is an ambitious project, which is based on very sophisticated technologies. In general, those financed with the ERC are projects that are expected to lead to a turning point if successful, even if it is not certain that it will be possible to achieve all the initial objectives".

From biopsy to the development of “organs in test tubes”

The work of the team, made up of biologists, medical researchers, bioinformaticians and chemists, will initially involve the analysis, through three different technologies, of muscle biopsies already collected over the years from cancer patients with or without cachexia, and from healthy people as a control group.

The first of the three technologies that will be used essentially allows us to study the level of gene expression in each single cell, how the tumor alters the signals that are exchanged within it and how these alterations can damage muscle tissue and determine the onset of cachexia.

“The second technology is spatial transcriptomics,” Sandri continues, “which allows us to see, in a tissue section, where these genes are expressed and how cells interact with each other.” The third, finally, concerns the development of organoids in vitro, again starting from tissues taken from patients. It involves reconstructing the patient’s neuromuscular tissue, made up of muscle cells and motor neurons, in a test tube.

Towards RNA-based therapies

“This will allow us to test in vitro, before moving on to clinical trials, the possible RNA-based therapies that we are trying to develop,” continues the expert. In particular, the research group is working on the development of small RNA fragments, consisting of about twenty nucleotides, that modulate the expression of certain genes (and more precisely the synthesis of specific proteins encoded by those genes) to counteract the mechanisms underlying the onset of cachexia. The target of these RNA fragments are not the genes themselves, but the messenger RNA that carries the information necessary for the expression of proteins.

This is the second 'soul' of the research project, which will continue in parallel with the first. For now, the technique has been tested on animal models and is already used for therapeutic purposes in some genetic diseases, such as muscular dystrophy. The team's aim at the moment is to test different types of vectors that can convey the RNA fragments in an effective and especially specific way towards the muscle tissue, without impacting other organs.

The importance of funding

This type of research has very high costs. To give an example, applying the first of the three analysis technologies mentioned on eight samples costs from 50 to 70 thousand euros. Let's then imagine expanding the cohort of patients to 200, 300 people. "Funding is essential, also to pay the people who carry out the analyses we talked about - concludes Sandri -. But beyond the economic aspect - concludes the researcher - receiving ERC funding is also an opportunity to network and get in touch with cutting-edge laboratories in our research field".