A new approach using two recombinant strains of adeno–associated virus (AAV) may help solve a vexing problem in gene therapy—controlling the expression of a therapeutic gene once it has been delivered to target cells. The method, reported in Science (283 :88–91, 1999) capitalizes on the ability of the drug rapamycin to bind simultaneously to two different protein sequences. By attaching the two sequences to DNA binding and transcriptional activation domains, scientists have created a pair of recombinant proteins that join to form a transcriptional activator only in the presence of the drug. The two–part activator was delivered to muscle cells in one AAV vector, while a separate AAV vector carried a gene encoding erythropoietin. In immunocompetent mice and rhesus monkeys, cells co–infected with the two viruses expressed high levels of erythropoietin when animals were given rapamycin. "The properties of this system are that when it's off it's off, when you want to induce it, it induces to levels that are as high as what you achieve with a high–level constitutive promoter, [and] the extent of the induction is proportional to the dose of the drug that you give," explains James Wilson, senior author on the new study. The technique has been licensed to a joint venture between ARIAD Pharmaceuticals (Cambridge, MA) and Genovo (Philadelphia, PA).