Basic Science
Zinc-finger nucleases for somatic gene therapy: the next frontier
Rahman SH, Maeder ML, Joung JK, Cathomen T. Hum Gene Ther. 2011 Aug;22(8):925-33.
Zinc-finger nucleases are a powerful tool that can be used to edit the human genome ad libitum. The technology has experienced remarkable development in the last few years with regard to both the target site specificity and the engineering platforms used to generate zinc-finger proteins. As a result, two phase I clinical trials aimed at knocking out the CCR5 receptor in T cells isolated from HIV patients to protect these lymphocytes from infection with the virus have been initiated. Moreover, zinc-finger nucleases have been successfully employed to knockout or correct disease-related genes in human stem cells, including hematopoietic precursor cells and induced pluripotent stem cells. Targeted genome engineering approaches in multipotent and pluripotent stem cells hold great promise for future strategies geared toward correcting inborn mutations for personalized cell replacement therapies. This review describes how zinc-finger nucleases have been applied to models of gene therapy, discusses the opportunities and the risks associated with this novel technology, and suggests future directions for their safe application in therapeutic genome engineering.
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Editor’s note: What are zinc-finger nucleases and why should we care? Zinc finger nucleases are artificial nucleases that have two functional domains¾one to recognize DNA and the other to cut it. They can cleave DNA, breaking both strands, at a specifically chosen target gene. Double-stranded breaks trigger one of two damage responses¾one simply puts the DNA back together while the other uses a donor DNA sequence to repair the break and correct a pre-existing genetic defect at the same time. This is not science fiction. Several knockout animal models have been created, such as the SCID (severe combined immunodeficiency) rat, that permit the study of various diseases. Two phase 1 trials are underway in people living with HIV to assess the safety of zinc-finger-nuclease knockout of the CCR5 receptor on chromosome 3. When this CD4+ cell receptor is deformed or absent, as in the naturally occurring CCR5deltaΔ mutation, people are largely protected from HIV infection. The idea is to reduce the capacity of HIV to dock and enter target cells. There is still much to learn, for example, to prevent the vectors carrying zinc-finger nucleases from integrating into our own genome and to ensure efficient and precise targeting of the correct DNA sites. Zinc-finger nucleases represent a promising advance-a tool to edit the human genome-that should get us all thinking about what the future might look like!
