Chapter 23. Novel Gene Switches for the Regulation of Gene Expression

Abstract

Publisher Summary Most gene expression systems currently under development for gene therapy applications, whether viral or nonviral, produce therapeutic proteins constitutively and provide no means to regulate the dose of the therapeutic gene. Thus, there is a recognized need for gene expression systems that can be tightly controlled. Recently, a number of gene expression systems have been developed that can be regulated by the administration of specific small molecule drugs. These systems require the expression of genetically engineered regulatory proteins that function as molecular switches or gene switches. This chapter describes a number of novel gene switches and discusses their potential use for in vivo human gene therapy. As understanding of gene transcription has increased, it has become possible to design gene expression systems that regulate the expression of exogenously-administered target genes by controlling the interaction of transcription factors (TFs), with specific response elements in the target gene's promoter or enhancer. Most approaches use similar strategies and involve the genetic engineering of chimeric transcription factors that contain a domain capable of binding to a specific response element in the promoter/enhancer of the target gene (DNA-binding domain), a domain capable of binding a specific ligand or small molecule drug to regulate the DNA binding activity (ligand-binding domain), and a domain capable of stimulating or repressing the transcriptional process (transactivation or transrepression domain). These chimeric transcription factors function as gene switches because they are capable of switching the transcription of a target gene on or off in response to administration of the ligand or small molecule drug. Other successful approaches to the regulated target gene expression are based on the generation of novel, chimeric transcription factors, derived from either bacterial repressor proteins or mammalian transcription factors. The chapter includes discussion of these two types of gene switches.