Pharmacologic transgene control systems for gene therapy

Abstract

Pharmacologic transgene-expression dosing is considered essential for future gene therapy scenarios. Genetic interventions require precise transcription or translation fine-tuning of therapeutic transgenes to enable their titration into the therapeutic window, to adapt them to daily changing dosing regimes of the patient, to integrate them seamlessly into the patient's transcriptome orchestra, and to terminate their expression after successful therapy. In recent years, decisive progress has been achieved in designing high-precision trigger-inducible mammalian transgene control modalities responsive to clinically licensed and inert heterologous molecules or to endogenous physiologic signals. Availability of a portfolio of compatible transcription control systems has enabled assembly of higher-order control circuitries providing simultaneous or independent control of several transgenes and the design of (semi-)synthetic gene networks, which emulate digital expression switches, regulatory transcription cascades, epigenetic expression imprinting, and cellular transcription memories. This review provides an overview of cutting-edge developments in transgene control systems, of the design of synthetic gene networks, and of the delivery of such systems for the prototype treatment of prominent human disease phenotypes.

Drug-inducible remote control of gene expression by probiotic Escherichia coli Nissle 1917 in intestine, tumor and gall bladder of mice

“…On the other hand, inducible promoters that do not fulfill the criteria of tight control might be modifiable [25]. Moreover, advancing insights into natural promoter systems might allow rational design of artificial IVRC gene switches [26].…”

Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System

“…83 Different types of inducible transcription systems, in which transgene expression is modulated by small molecules, have been engineered into the AAV backbone, essentially by adapting the systems broadly used in other vector platforms. 84 Currently, the 2 most considered methods to achieve pharmacologically inducible transcription are the tetracycline-inducible (TetOn) or tetracycline-repressible (TetOff) systems 85 and the method based on rapamycin-induced dimerization of FKBP12 (FK506 binding protein 12)-and mammalian target of rapamycin-derived proteins. 86 In the former case, regulation is based on 2 transcriptional units, one coding for the tetracycline regulator under the control of a constitutive promoter and the other containing the transgene downstream of a tetracycline-binding promoter ( Figure 4A and 4B).…”

Controlling transgene expression in subcutaneous implants using a skin lotion containing the apple metabolite phloretin

“…ynthetic mammalian expression systems, which enable reversible and adjustable transgene expression, have been essential for recent advances in (i) functional genomic research (1), (ii) drug discovery (2,3), (iii) manufacturing of difficult-toproduce protein therapeutics (4,5), (iv) the design of synthetic gene networks replicas reaching the complexity of electronic circuits (6)(7)(8)(9), and (v) gene therapy applications (10)(11)(12).…”