The traditional gene-therapy approach relies on the delivery of a therapeutic transgene into a cell, typically to compensate for a gene that is not functional owing to a genetic defect. But why not just correct the genetic defects directly? The answer used to be that there was no methodology for making precise genetic modifications in a highly efficient manner. That is changing now. Over the last decade, researchers have devised a way to stimulate the natural DNA-repair mechanisms of the cell to occur at any desired site in the genome. The enabling technological advance has been the development of programmable nucleases, which use re-engineered ZF (zinc-finger) DNA-binding domains to cut the DNA in a living cell at a precise user-defined location. These methods have been shown to produce genetic modifications at frequencies of >1 correct event per ten treated cells, representing a 100 000-fold stimulation of targeted gene repair. The first Phase I clinical trial of a therapeutic ZFN (zinc-finger nuclease) is scheduled for 2008.

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