Gene therapy on demand: site specific regulation of gene therapy

Abstract

Since 1990 when the first clinical gene therapy trial was conducted, much attention and considerable promise have been given to this form of treatment. Gene therapy has been used with success in patients suffering from severe combined immunodeficiency syndromes (X-SCID and ADA-deficiency), Leber's congenital amaurosis, hemophilia, β-thalassemia and adrenoleukodystrophy. Last year, the first therapeutic vector (Glybera) for treatment of lipoprotein lipase deficiency has been registered in the European Union. Nevertheless, there are still several numerous issues that need to be improved to make this technique more safe, effective and easily accessible for patients. Introduction of the therapeutic gene to the given cells should provide the level of expression which will restore the production of therapeutic protein to normal values or will provide therapeutic efficacy despite not fully physiological expression. However, in numerous diseases the expression of therapeutic genes has to be kept at certain level for some time, and then might be required to be switched off to be activated again when worsening of the symptoms may aggravate the risk of disease relapse. In such cases the promoters which are regulated by local conditions may be more required. In this article the special emphasis is to discuss the strategies of regulation of gene expression by endogenous stimuli. Particularly, the hypoxia- or miRNA-regulated vectors offer the possibilities of tight but, at the same time, condition-dependent and cell-specific expression. Such means have been already tested in certain pathophysiological conditions. This creates the chance for the translational approaches required for development of effective treatments of so far incurable diseases.

Keywords: 3′UTR; 3′untranslated region; 5-FC; 5-fluorocytosine; ARE; BVR; CD; DBD; DNA binding domain; Epo; GALC; HIF; HO-1; HRE; HSC; HSV TK; Heme oxygenase-1; Hypoxia; Keap 1; Kelch like ECH-associated protein 1; MLC2v; Nrf2; ODD; Oxidative stress; PHDs; ROS; Src homology domain-2 containing tyrosine phosphatase-1; Tet; Tet-Off/Tet-On systems; TetO; TetR; VEGF; WAS; Wiskott–Aldrich syndrome; antioxidant response element; biliverdin reductase; cytosine deaminase; erythropoietin; galactocerebrosidase; hematopoietic stem cells; heme oxygenase-1; herpes simplex virus thymidine kinase; hypoxia inducible factor; hypoxia response element; iPSCs; induced pluripotent stem cells; miRNA; miSHP-1; microRNA; myosin light chain 2 ventricular/cardiac muscle isoform; oxygen dependent degradation domain; prolyl hydroxylases; rTetR; reactive oxygen species; reverse tetracycline controlled transactivator; reverse tetracycline repressor; rtTA; tTA; tTS; tetracycline; tetracycline controlled transactivator; tetracycline controlled transcriptional silencer; tetracycline operator; tetracycline repressor; vascular endothelial growth factor.