To carry out their activities, Research Teams of the Frédéric Joliot Institute for Life Sciences have developed high-profile technological platforms in many areas : biomedical imaging, structural biology, metabolomics, High-Throughput screening, level 3 microbiological safety laboratory...
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We develop broad-spectrum inhibitors of bacterial toxins that interfere with the intracellular trafficking machinery. As a result, these inhibitors have also antiviral, anti-intracellular bacteria and anti-parasitic activities. We also develop a fragment of the diphtheria toxin as an inhibitor of HB-EGF for the treatment of rapidly progressive glomerulonephritis, a rare kidney disease.
The Toxins, transport and therapeutic innovation group is involved in two main research topics.
We develop several families of molecules blocking intracellularly-acting plant and bacterial toxins. These molecules act as broad-spectrum inhibitors of toxins and various pathogens that use intracellular trafficking pathways to invade cells. As a result, these inhibitors have also antiviral, anti-intracellular bacteria and anti-parasitic activities. These inhibitors were discovered since 2010: Retro-1, Retro-2, ABMA and C910 (Stechmann et al., 2010; Wu et al., 2017; Wu et al., 2021). Since 2013, for each of them, we have:
Rapidly progressive glomerulonephritis is a rare kidney disease in which the filtration units of the kidneys, the glomeruli, are irretrievably destroyed. The disease is due to an (auto)-immune aggression of the glomeruli involving autoantibodies or antibacterial antibodies. The immune aggression activates the expression of a growth factor, HB-EGF, by podocytes, the specialized cells forming the filtration barrier of the kidney. As a result, the podocytes and glomerular parietal cells dedifferentiate and proliferate, destroying the glomeruli. Blocking HB-EGF protect the glomeruli despite the persistence of autoantibodies. Current treatments are based solely on immunosuppression and do no protect the kidney from HB-EGF. As a consequence, the disease is poorly managed leading to a high requency of terminal kidney failure or death.
The membrane precursor form of HB-EGF is also the natural receptor for the diphtheria toxin. Thus, we engineered, from a fragment of the diphtheria toxin, a powerful inhibitor of HB-EGF called DTR8, capable of blocking the proliferation of podocytes.
An initial proof of concept study in an animal model of the disease showed that DTR8 can protect the glomeruli and prevent kidney failure. Our goal is now to turn DTR8 into a drug for the treatment of rapidly progressive glomerulonephritis.
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.