Gene therapy progress and prospects: transcription regulatory systems

Abstract

The clinical efficacy and safety as well as the application range of gene therapy will be broadened by developing systems capable of finely modulating the expression of therapeutic genes. Transgene regulation will be crucial for maintaining appropriate levels of a gene product within the therapeutic range, thus preventing toxicity. Moreover, the possibility to modulate, stop or resume transgene expression in response to disease evolution would facilitate the combination of gene therapy with more conventional therapeutic modalities. The development of ligand-dependent transcription regulatory systems is thus of great importance. Here, we summarize the most recent progress in the field.

Drug-inducible and simultaneous regulation of endogenous genes by single-chain nuclear receptor-based zinc-finger transcription factor gene switches

“…These chimeric transregulators dimerize upon drug addition and eventually undergo conformational changes that result in control of a target promoter ( Figure 1). As these systems have been based on naturally existing DBDs of definite DNA sequence specificity, use has been restricted to regulation of exogenously delivered transgenes or reporter genes 23 (Figure 1a). Use of ZF-based domains as the DBD of the chimeric transregulator allows targeting of virtually any sequence in a promoter, minimizing endogenous cross-reactivity and potentially allowing regulation of any desired chromosomal promoter.…”

Autoregulatory lentiviral vectors allow multiple cycles of doxycycline-inducible gene expression in human hematopoietic cells in vivo

“…Among the available approaches, the tetracycline (Tc)-inducible gene regulation system has been proven efficient, both in vitro and in vivo. 1,2 The prokaryotic Tc-inducible gene regulation system is based on two elements of the Tn10 Tc resistance operon of Escherichia coli: the repressor protein (TetR) and its target DNA sequence, the tet operator (tetO). 3,4 In the absence of Tc, TetR dimerizes and binds to tetO, blocking transcription of this operon.…”

Gene Therapy Progress and Prospects – Vectorology: design and production of expression cassettes in AAV vectors

“…The regulatory system based on the use of small molecules, such as tetracycline or doxycycline, is the most widely used and represents a versatile system for gene therapy applications. 14,15 However, leaking activity of the Tet regulatory system (tet-on and tet-off) has been shown to occur. It has been hypothesized to be due to the proximity of either the enhancer/promoter present within AAV ITR or the promoter driving the expression of the tet regulator.…”