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Proceedings/Recueil Des Communications Année : 2017

Regulating the expression of therapeutic transgenes by controlled intake of dietary essential amino acids

Alain Bruhat
Cedric Chaveroux
Valerie Carraro
  • Fonction : Auteur
  • PersonId : 1204423
Céline Jousse
Julien Averous
Laurent Parry
  • Fonction : Auteur
  • PersonId : 1204424
Pierre Fafournoux

Résumé

Widespread application of gene therapy will depend on the development of simple methods to regulate the expression of therapeutic genes. Here we harness an endogenous signaling pathway to regulate therapeutic gene expression through diet. The GCN2-ATF4 signaling pathway is specifically activated by deficiencies in any essential amino acid (EAA). EAA deficiency leads to rapid expression of genes regulated by AT F4-binding cis elements called Amino Acid Response Elements (AARE). We found that therapeutic genes under the control of optimized AAREs had low basal expression and high-induced expression. Briefly, after consumption of a diet deficient in one EAA, the blood concentration of the limiting EAA decreases rapidly and greatly, triggering the activation of the GCN2-ATF4 pathway and then the AARE-dependent transcription. We showed that the AARE-driven expression system can efficiently regulate the expression of a luciferase reporter gene in liver, pancreas and brain. For regulation of therapeutic transgenes over long-time periods, we performed pulses of EAA-deprived diet,swapping each of the lacking EAA. We applied our system to regulate the expression of the proapoptotic cytokine TRAIL (TNFSF10) in the context of glioma therapy and found that intermittent activation of this gene by E AA-deficient meals retained its therapeutic efficacy while abrogating its toxic effects on normal tissue. Our system may be particularly well suited for intermittent regulation of therapeutic transgenes over short or long time periods.It exhibits the desirable properties for translation from the laboratory to clinical practice. Reference: Chaveroux et al (2016) Nature Biotechnology Jul;34(7):746-51

Dates et versions

hal-02786230 , version 1 (04-06-2020)

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Citer

Alain Bruhat, Cedric Chaveroux, Valerie Carraro, Céline Jousse, Julien Averous, et al.. Regulating the expression of therapeutic transgenes by controlled intake of dietary essential amino acids. European Society of Gene and Cell Therapy (ESCGT) Congress, Oct 2017, Berlin, Germany. 28 (12), Mary Ann Liebert, pp.A61-A61, 2017, Human Gene Therapy, ⟨10.1089/hum.2017.29055.abstracts⟩. ⟨hal-02786230⟩
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