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Dernière mise à jour : Mai 2018

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Human Nutrition Unit

Zone de texte éditable et éditée et rééditée

To transfer

     

Transfer of the research finding to gene-therapy



NUTRIREG: a new modular gene expression system through nutritional intervention 


  • Exploitation of the endogenous GCN2-eIF2α-ATF4 signaling pathway
  • Consumption of a essential amino acid (EAA)-deficient diet leads to a decrease of the blood concentration of this EAA. When this concentration falls below a certain threshold, the GCN2-eIF2α-ATF4 signaling pathway leads to the translation of the ATF4 transcription factor mRNA in the cells of targeted tissues. This factor binds to the AARE (Amino Acid Reponse Element) sequences in the promoter of specific target genes leading to their expression, and allows the organism to adapt to EAA deficiency (transport of EAA, autophagy, etc.).

  • NUTRIREG is a breakthrough technology that could be applied to situations where it is key to modulate the expression of a transgene.
  • The NUTRIREG technology involves (1) an expression cassette containing a drug gene under the control of an artificial promoter based on AARE sequences and (2) a diet lacking one EAA. The expression cassette is delivered to the target tissue through a viral vector and the expression of the drug gene is induced by the consumption of the EAA-deficient diet. Interestingly, the transgene expression can be quickly turned-off by consuming the missing EEA.

  • Zoom on a proof of concept of NUTRIREG use
  • TRAIL encodes for a proapoptotic protein that targets tumor cells. The viral vector containing the AARE-TRAIL expression cassette was injected into a mouse subcutaneous tumor. The animals were fed with alternating EAA-deficient diets (vs Control). TRAIL protein was expressed and allowed tumor growth to be stopped, as shown by monitoring the growth (Figure a) and measuring size of the tumor (Figure b) (Chaveroux et al. Nature Biotech, 2016)

  • NUTRIREG applicable in gene therapy
  • This technology has a unique advantage compared to other inducible systems: it is not toxic and is therefore potentially usable in human medicine. NUTRIREG is functional in several tissues. This spatio-temporal modulation opens up new avenues in gene therapy for the treatment of a large number of pathologies (cancer, neurodegenerative diseases, rare diseases, ophthalmology, cell therapy, etc.).

    This technology is the result of 20 years of fundamental research conducted within the team and has been patented by INRAE ​​and CNRS. 
    If you are interested in NUTRIREG technology, you can contact Pierre FAFOURNOUX, Alain BRUHAT or Cyrielle VITURET.

  • Investigators
  • Pierre FAFOURNOUXAlain BRUHATCyrielle VITURET, Audrey FAURE and Fida AZAR.