Inducible gene expression in mammalian cells

Abstract

Publisher Summary Artificial control systems for adjusting transgene expression in mammalian cells, animals and eventually humans have generated tremendous impact on different areas of modern biomedical engineering ranging from basic gene-function analysis, drug discovery, drug testing in animals, the design of animal-based human disease models and biopharmaceutical manufacturing to gene therapy and tissue engineering strategies. Heterologous gene regulation systems have become an integral part of current spearhead therapeutic technologies focusing on production and delivery of therapeutic proteins where they are needed in the human body. Only a few of these systems have the assets for human therapeutic use including absence of any interference with endogenous regulatory networks, and graded as well as rapid response characteristics showing low basal and high maximum expression levels following administration of a clinically licensed drug (e.g., antibiotics, immunophilins and steroid hormones). The chapter focuses on these human-compatible systems that are currently competing in preclinical studies for optimal performance in adjusting expression of a single therapeutic (model) gene, (e.g., erythropoietin, insulin or human growth hormone). Recent initiatives to combine several compatible heterologous gene regulation systems have exemplified that complex artificial gene control configurations such as regulatory cascades and networks will develop in the next years from concept studies to a therapeutic reality. Such multiregulated multigene metabolic engineering will enable optimal integration of next-generation gene interventions in endogenous proliferation-, differentiation- and apoptosis-regulatory networks to achieve cell phenotypes designed to improve the understanding and therapy of currently untreatable human diseases. This chapter discusses different human-compatible heterologous gene regulation systems, their adaptation to specific expression configurations, and their potential to be integrated into higher order control systems to achieve next-generation gene therapy and tissue engineering strategies.