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