Gene transfer: the challenge of regulated gene expression

Gene therapy is expected to have a major impact on human healthcare in the future. However, precise regulation of therapeutic gene expression in vivo is still a challenge. Natural and synthetic enhancer-promoters (EPs) can be utilized to drive gene transcription in a temporal, spatial or environmental signal-inducible manner in response to heat shock, hypoxia, radiation, chemotherapy, epigenetic agents or viral infection. To allow tightly regulated expression, a regulatable gene-expression system can also be implemented. Most of these systems are based on small molecule (drug)-responsive artificial transactivators. In this review, we aim to provide a brief overview of the classes of EPs and regulatable systems, along with lessons learned from these studies. We highlight the potential applications in gene transfer, gene therapy for cancer and genetic disease and the future challenges for clinical applications.