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Nat Biotechnol. 2016 Jul;34(7):746-51. doi: 10.1038/nbt.3582. Epub 2016 Jun 6.

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

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Institut National de la Recherche Agronomique (INRA), UMR-1019 Nutrition Humaine, Genes-Nutrients team, Centre de Clermont-Theix, Université Clermont-Ferrand 1, 63122 Saint Genès Champanelle, France.
CRCT, Université de Toulouse, Inserm, UPS, Toulouse, France.
Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique (CNRS) UPR4301, Université d'Orléans and Institut National de la Santé Et de la Recherche Médicale (INSERM), Orléans, France.
CNRS UMR7225, INSERM U1127, Université Pierre et Marie Curie, Institut du Cerveau et de la Moelle (ICM), Biotechnology and Biotherapy Team, Paris, France.
Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.


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-eIF2α signaling pathway is specifically activated by deficiencies in any essential amino acid (EAA); EAA deficiency leads to rapid expression of genes regulated by ATF4-binding cis elements. We found that therapeutic genes under the control of optimized amino acid response elements (AAREs) had low basal expression and high induced expression. We applied our system to regulate the expression of TNFSF10 (TRAIL) in the context of glioma therapy and found that intermittent activation of this gene by EEA-deficient meals retained its therapeutic efficacy while abrogating its toxic effects on normal tissue. The GCN2-eIF2α pathway is expressed in many tissues, including the brain, and is highly specific to EAA deficiency. Our system may be particularly well suited for intermittent regulation of therapeutic transgenes over short or long time periods.

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