Molecular Switch for Controlled Gene Therapy

This application describes construction of a vector for a gene therapy that can be incorporatedinto somatic cells in vivo and then regulated by administration of an oral, non-toxic, and widelybioavailable drug. The "gene switch" is based on a derived mutant of the progesterone receptor thatis activated by progesterone antagonists, but is not activated by progesterone agonists or other steroids.This mutant will be recombined with DNA binding sequences that recognize a unique element not foundin human cells. The gene encoding the gene switch under the control of a constitutive promoter will beintroduced into cells with the therapeutic gene and will be regulated specifically and selectively byanti-progestins at low levels that will exert no anti-progesterone effect. The vector will be validatedusing a tyrosine hydroxylase gene controlled by the gene switch. Cells containing these genes will beused to treat an animal model of Parkinson's disease. This will serve as a model for vectors that maybe used to treat complex, neurodegenerative diseases where tight control of gene expression will beimportant.