Regulatable gene expression systems for gene therapy applications: progress and future challenges

GOVERDHANA; PUNTEL; XIONG; ZIRGER; BARCIA; CURTIN; SOFFER; MONDKAR; KING; HU; SCIASCIA; CANDOLFI; GREENGOLD

MOLECULAR THERAPY (PRINT)

NATURE PUBLISHING GROUP

Año: 2005 p. 189 - 211

1525-0016

Gene therapy aims to revert diseased phenotypes by the use of both viral and nonviral genedelivery systems. Substantial progress has been made in making gene transfer vehicles moreefficient, less toxic, and nonimmunogenic and in allowing long-term transgene expression. One ofthe key issues in successfully implementing gene therapies in the clinical setting is to be able toregulate gene expression very tightly and consistently as and when it is needed. The regulationought to be achievable using a compound that should be nontoxic, be able to penetrate into thedesired target tissue or organ, and have a half-life of a few hours (as opposed to minutes or days)so that when withdrawn or added (depending on the regulatable system used) gene expressioncan be turned --on --or --off --quickly and effectively. Also, the genetic switches employed shouldideally be nonimmunogenic in the host. The ability to switch transgenes on and off would be ofparamount importance not only when the therapy is no longer needed, but also in the case of thedevelopment of adverse side effects to the therapy. Many regulatable systems are currently underdevelopment and some, i.e., the tetracycline-dependent transcriptional switch, have been usedsuccessfully for in vivo preclinical applications. Despite this, there are no examples of switches thathave been employed in a human clinical trial. In this review, we aim to highlight the mainregulatable systems currently under development, the gene transfer systems employed for theirexpression, and also the preclinical models in which they have been used successfully. We alsodiscuss the substantial challenges that still remain before these regulatable switches can beemployed in the clinical setting.