Their findings are published in PNAS.
The scientists have developed a more efficient way to target genes using synthetic proteins. Many biological processes are determined by switching genes on or off. Genes give instructions for making the proteins involved in these processes. This regulation of gene expression is controlled by regulatory proteins called transcription factors.
Sir Aaron Klug, of the Medical Research Council's Laboratory of Molecular Biology in Cambridge, devised these synthetic transcription factors called zinc-finger nucleases based on a naturally occuring design. These zinc-fingered nucleases have the capacity to recognise specific sequences of DNA which makes them extremely good at targeting particular genes without affecting others.
Sir Aaron explains: The beauty of zinc-finger nucleases lies in their simplicity. Where other methods are long, arduous and often messy, it is relatively easy to switch off genes using this method. The zinc-finger design allows us to target a single gene, while the nuclease disrupts the gene. The single step process is extremely quick and reliable and opens up exciting possibilities for research and gene therapy.These findings confirm that this method of gene targeting will present an efficient option for scientists to create knock-out animals for research. Animal trials are already under way to use the technique to knock out the receptor of HIV in T-cells of AIDS patients, so leading to a supply of non-infectable T-cells, which will combat HIV and the other infections which occur in AIDS patients. Clinical trials are also in progress for stimulating the growth of new arteries in patients suffering from obstruction of the blood vessels in the limbs.
This is a powerful technology for intervening in gene expression in health or disease and therapeutic applications are planned for other diseases by Sangamo BioSciences.
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"If we can prevent ?-TRCP from binding to REST, we may be able to treat certain tumors that display neuronal gene expression profiles," says Elledge, who is also a member of the HMS-Partners HealthCare Center for Genetics and Genomics and investigator with the Howard Hughes Medical Institute. "Such profiles are remarkably common in epithelial cancers, such as breast cancer and ovarian cancer."
"This discovery is particularly exciting because the scientific community knows how to target enzymes that add and remove phosphate groups from proteins with small molecules," says Westbrook. "Big pharmaceutical companies have devoted lots of resources to accomplishing this task."
Information about the interaction between ?-TRCP and REST might also aid researchers in the embryonic stem cell field.
"It's hard to control the differentiation of embryonic stem cells into specialized cells such as neurons," says Westbrook. "If one could prevent ?-TRCP from tagging REST for destruction, one could potentially keep embryonic stem cells from turning into neurons. Alternatively, one might be able to make neurons more efficiently by quickening REST destruction."
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