title: Regulatable gene expression systems for gene therapy applications: progress and future challenges.
abstract: Gene therapy aims to revert diseased phenotypes by the use of both viral and nonviral gene delivery systems. Substantial progress has been made in making gene transfer vehicles more efficient, less toxic, and nonimmunogenic and in allowing long-term transgene expression. One of the key issues in successfully implementing gene therapies in the clinical setting is to be able to regulate gene expression very tightly and consistently as and when it is needed. The regulation ought to be achievable using a compound that should be nontoxic, be able to penetrate into the desired target tissue or organ, and have a half-life of a few hours (as opposed to minutes or days) so that when withdrawn or added (depending on the regulatable system used) gene expression can be turned "on" or "off" quickly and effectively. Also, the genetic switches employed should ideally be nonimmunogenic in the host. The ability to switch transgenes on and off would be of paramount importance not only when the therapy is no longer needed, but also in the case of the development of adverse side effects to the therapy. Many regulatable systems are currently under development and some, i.e., the tetracycline-dependent transcriptional switch, have been used successfully for in vivo preclinical applications. Despite this, there are no examples of switches that have been employed in a human clinical trial. In this review, we aim to highlight the main regulatable systems currently under development, the gene transfer systems employed for their expression, and also the preclinical models in which they have been used successfully. We also discuss the substantial challenges that still remain before these regulatable switches can be employed in the clinical setting.
authors.affiliation: Department of Medicine, Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California at Los Angeles, Davis Building, Room 5090, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: S
authors.initials: S
authors.lastname: Goverdhana
authors.forename: M
authors.initials: M
authors.lastname: Puntel
authors.forename: W
authors.initials: W
authors.lastname: Xiong
authors.forename: J M
authors.initials: JM
authors.lastname: Zirger
authors.forename: C
authors.initials: C
authors.lastname: Barcia
authors.forename: J F
authors.initials: JF
authors.lastname: Curtin
authors.forename: E B
authors.initials: EB
authors.lastname: Soffer
authors.forename: S
authors.initials: S
authors.lastname: Mondkar
authors.forename: G D
authors.initials: GD
authors.lastname: King
authors.forename: J
authors.initials: J
authors.lastname: Hu
authors.forename: S A
authors.initials: SA
authors.lastname: Sciascia
authors.forename: M
authors.initials: M
authors.lastname: Candolfi
authors.forename: D S
authors.initials: DS
authors.lastname: Greengold
authors.forename: P R
authors.initials: PR
authors.lastname: Lowenstein
authors.forename: M G
authors.initials: MG
authors.lastname: Castro
mesh_terms: D005786:Gene Expression Regulation; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods* / Q000639:trends; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D013752:Tetracycline; D014161:Transduction, Genetic; D019076:Transgenes; D014780:Viruses / Q000235:genetics
chemical_list: D013752:Tetracycline