ZINC FINGER NUCLEASES: TAILOR-MADE FOR GENE THERAPY

Genome editing with the use of zinc finger nucleases (ZFNs) has been successfully applied to a variety of eukaryotic cells. Furthermore, the proof of concept for this approach has been extended to diverse animal models from Drosophila to mice. Engineered ZFNs are able to specifically target and manipulate disease-causing genes through site-specific double-strand DNA breaks followed by non-homologous end joining or homologous recombination mechanisms. Consequently, this technology has considerable flexibility, which can result in either a gain or loss of function of the targeted gene. In addition to this flexibility, gene therapy with ZFNs may enable persistent long-term gene modification without continuous transfection - a potential advantage over RNA interference or direct gene inhibitors. With systemic viral delivery systems, this gene-editing approach corrected mutant coagulation factor IX in mouse models of hemophilia. Moreover, phase I clinical trials have been initiated with ZFNs in patients with glioblastoma and HIV. Thus, this emerging field has significant promise as a therapeutic strategy for human genetic diseases, infectious diseases and oncology. In this article, we will review recent advances and potential risks in ZFN gene therapy.