Regulatable gene expression systems for gene therapy applications: progress and future challenges
| Autor: | Weidong Xiong, Carlos Barcia, James F. Curtin, Pedro R. Lowenstein, Diana S. Greengold, Jeffrey M. Zirger, Shyam Goverdhana, Gwendalyn D. King, Marianela Candolfi, Sonali Mondkar, Mariana Puntel, Jiang Hu, E. B. Soffer, Sandra A. Sciascia, Maria G. Castro |
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| Rok vydání: | 2005 |
| Předmět: |
Genetic enhancement
Transgene Genetic Vectors Computational biology Gene delivery Biology Article Transduction (genetics) Transduction Genetic Gene expression Drug Discovery Genetics Humans Transgenes Gene Molecular Biology Regulation of gene expression Pharmacology Gene targeting Genetic Therapy Tetracycline Gene Expression Regulation Gene Targeting Viruses Molecular Medicine |
| Zdroj: | Molecular Therapy. 12(2):189-211 |
| ISSN: | 1525-0016 |
| DOI: | 10.1016/j.ymthe.2005.03.022 |
| Popis: | 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the desired target tissue or organ, and have a half-life of a few hours (as opposed to minutes or days) so that when withdrawn or added (depending on the regulatable system used) gene expression can be turned “on” or “off” quickly and effectively.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. |
| Databáze: | OpenAIRE |
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