Regulating the expression of therapeutic transgenes by controlled intake of dietary essential amino acids - Université Pierre et Marie Curie Accéder directement au contenu
Article Dans Une Revue Nature Biotechnology Année : 2016

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

Cedric Chaveroux
Alain Bruhat
Céline Jousse
Julien Averous

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-eIF2 a 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- eIF2 a 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.
Fichier non déposé

Dates et versions

hal-01594469 , version 1 (26-09-2017)

Identifiants

Citer

Cedric Chaveroux, Alain Bruhat, Valerie Carraro, Céline Jousse, Julien Averous, et al.. Regulating the expression of therapeutic transgenes by controlled intake of dietary essential amino acids. Nature Biotechnology, 2016, 34, pp.746-751. ⟨10.1038/nbt.3582⟩. ⟨hal-01594469⟩
241 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More