Nature Medicine
2, 1028 - 1032 (1996)
doi:10.1038/nm0996-1028
A humanized system for pharmacologic control of gene expressionVictor M. Rivera1, Tim Clackson1, Sridaran Natesan1, Roy Pollock1, Jane F. Amara1, Terence Keenan1, Shannon R. Magari1, Tom Phillips1, Nancy L. Courage1, Franklin Cerasoli Jr.1, Dennis A. Holt1
& Michael Gilman1, 2
1ARIAD Gene Therapeutics, 26 Landsdowne Street, Cambridge, Massachusetts 02139, USA
2Correspondence should be addressed to M.G. Gene therapy was originally conceived as a medical intervention to replace or correct defective genes in patients with inherited disorders. However, it may have much broader potential as an alternative delivery platform for protein therapeutics, such as cytokines, hormones, antibodies and novel engineered proteins. One key technical barrier to the widespread implementation of this form of therapy is the need for precise control over the level of protein production. A suitable system for pharmacologic control of therapeutic gene expression would permit precise titration of gene product dosage, intermittent or pulsatile treatment, and ready termination of therapy by withdrawal of the activating drug. We set out to design such a system with the following properties: (1) low baseline expression and high induction ratio; (2) positive control by an orally bioavailable small−molecule drug; (3) reduced potential for immune recognition through the exclusive use of human proteins; and (4) modularity to allow the independent optimization of each component using the tools of protein engineering. We report here the properties of this system and demonstrate its use to control circulating levels of human growth hormone in mice implanted with engineered human cells.
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