Pierre-Louis Tharaux , 2021 Research Prize

Twenty-five years ago, Pierre-Louis Tharaux, back then a nephrologist, vowed to help bring kidney failure out of its therapeutic dead-end. Now a researcher, he is on the way to success with an innovative approach and a first treatment being trialed in patients: progress rewarded by the Research Prize.

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Portrait de Pierre-Louis Tharaux
Pierre-Louis Tharaux © Inserm / François Guénet

On a quest for kidney failure treatments

« Transplantation and dialysis can treat kidney diseases, but these are used at a late stage, when the organ is failing completely, states Pierre-Louis Tharaux, who co-leads with Éric Camerer the Kidney and vascular signalling: from development to disease team at the Paris Cardiovascular Research Center (Parcc, Unit 970 Inserm/Université de Paris). Research is needed in order to understand these diseases and find treatments that work at an earlier stage. » A conviction acquired from when he did his medical internship.

He therefore opted to do research but remains influenced by his work as a doctor. “Among patients who have, for example, diabetes, hypertension, or an autoimmune disease, some develop kidney failure to a more or less severe extent and others do not, he explains. This suggests that there are systems that govern our organs’ tolerance to attacks and which are potential therapeutic targets, in addition to treatments that target the very cause of the disease. »

Act early to preserve the kidneys

In the mid-2000s, as a young researcher, Tharaux was successful in his approach to sickle-cell disease, a genetic disease of the red blood cells, which can affect the kidneys. He showed that it is possible to modulate the tone and inflammation of the blood vessels and thus prevent them from being blocked by abnormal red blood cells1.

He became an Inserm Research Director in 2009 and refocused his work on the most severe non-genetic kidney diseases, with the aim being to preserve the glomeruli. The destruction of these key structures of the kidneys, responsible for filtering waste products from the blood excreted in the form of urine, leads to severe kidney failure.

His team combines fundamental and clinical research. It is supported by the European Research Council, the French Foundation for Medical Research and the French Foundation for Rare Diseases and collaborates in particular with the prestigious École Polytechnique as well as the German universities of Freiburg and Hamburg. In this way it has identified mechanisms showing that diseased glomeruli cells become agents of the disease. Among these agents, podocytes secrete a factor that promotes their own death2. In diabetes, their protein quality control system is deficient3. In autoimmune diseases, they become more susceptible to inflammation4–5. Finally, when a glomerulus is damaged, it sends signals to nearby cells which come to destroy it6.

Mosaïque de portraits des membres de l'équipe de Pierre-Louis Tharaux
From left to right and top to bottom: Anis Chaba, Johanna Comes, Julien Dang, Jean-Daniel Delbet, Léa Dionet, Christine Ibrahim, Alexandre Karras, Olivia Lenoir, Marie Quentin, Léa Resmini, Yann Salemkour, Benjamin Terrier © Inserm / François Guénet

Numerous mechanisms elucidated

However, these local mechanisms can all be modulated. In fact, we are going to start a clinical trial in autoimmune inflammatory diseases of the kidneys, by repurposing a diabetes drug, pioglitazone,” adds Tharaux who, in terms of potential treatments, has more than one string to his bow, having filed ten patents with the support of Inserm Transfert.

Finally, true to his approach, « at the start of the COVID-19 pandemic, due to the lack of antivirals available, we and other doctors and researchers suggested to the REACTing Consortium that we should test drugs to limit the destruction of organs infected by the virus, he relates. This is how the Corimuno-19 trials began – trials that showed the therapeutic value of tocilizumab, which is now recommended by the WHO.

Notes :
1: N. Sabaa et al. J Clin Invest., April 1, 2008; doi: 10.1172/JCI33308
2: G. Bollée et al. Nat Med. September 25, 2011; doi: 10.1038/nm.2491
3: O. Lenoir et al. Autophagy, 2015; doi: 10.1080/15548627.2015.1049799
4: C. Henique et al. Nat Commun., November 28, 2017; doi: 10.1038/s41467-017–01885‑7
5: C. Henique et al. J Am Soc Nephrol., May 21, 2015; doi: 10.1681/ASN.2014111080
6: H. Lazareth et al. Nat Commun., July 24, 2019; doi: 10.1038/s41467-019–11013‑2