Antiprogestin-controlled gene regulation systems, initially developed by Bert O'Malley and colleagues, are based on the unusual properties of certain truncated progesterone receptor ligand-binding domains (PR-LBDdelta19). These modified PR-LBDs have lost the ability to respond to progestins, but have gained the ability to respond to antiprogestins as agonists, rather than as antagonists. When a modified PR-LBD is joined to specific DNA-binding and transcription activator domains, the resultant chimeric protein functions as an antiprogestin-inducible transcription factor for transgenes linked to promoters with specific DNA-binding sites. Antiprogestin-inducible gene regulation systems have been used to regulate transgene expression in cultured cells, transgenic animals, and for in vivo gene transfer studies using viral- or plasmid-based vectors. We have designed a plasmid-based, muscle-specific GeneSwitch system that is delivered to skeletal muscle by electroporation and provides regulated erythropoietin (EPO) expression in mice and rats in a manner that is dependent on orally administered mifepristone (MFP). Regulation was effective at low doses of MFP and provided regulated biological responses (hematocrit changes) for more than 6 months. This plasmid-based, antiprogestin-inducible EPO/GeneSwitch system has the potential to be a convenient, long-lasting and effective gene-based therapy for the treatment of anemia.