Progress in transcriptionally targeted and regulatable vectors for genetic therapy.

Safety is an important consideration in the development of genetic therapy protocols; for example, proteins that are therapeutic in the context of one tissue may be harmful in another. This is particularly relevant to suicide gene strategies for cancer, which require in vivo delivery of DNA and which, in general, demand that the therapeutic product be limited as far as possible to malignant cells. This has led to a requirement for "transcriptionally targeted" vectors that can restrict the expression of the therapeutic sequence to appropriate cells. Furthermore, there may be a therapeutic window for certain proteins such that levels of expression below and above certain thresholds may be ineffective or toxic, respectively. Therefore, it would also be desirable to create vectors that allow exogenous control of expression, so that levels of the therapeutic protein can be raised or lowered according to therapeutic need. In the context of transcriptional targeting, one may sometimes use cis-acting sequences to limit transgene expression to the target cell type. In genetic therapy for cancer, for example, it may be possible to identify and use transcriptional control elements that drive expression of proteins unique to, or over-expressed in, malignant cells. These controls would greatly reduce collateral expression of the transgene, and hence reduce toxicity to healthy cells. With regard to exogenous control of expression subsequent to transduction, several synthetic gene regulation systems have now been produced. In these systems, an inducer or repressor acts on a synthetic transcription factor that recognizes motifs unique to the promoter of the transgene; this allows regulated expression of the therapeutic protein without nonspecific effects on cellular promoters. It is likely that a vector will soon be produced in which tissue-restricted expression of the synthetic transcription factor is combined with regulatable transgene expression thereby allowing precise control of therapeutic protein production in specific tissues via administration of an inducing or repressing agent.