Sangamo in the news
How zinc-finger proteins treat illness by aiming at a single gene
[March 18, 2008]
Mark Henderson, Science Editor [Times Online]
A new way of turning genes on and off, pioneered by a Nobel prize-winning British scientist, is promising to transform treatment of conditions such as HIV/Aids, heart disease and diabetes.
The technique, devised by Sir Aaron Klug, of the Laboratory of Molecular Biology in Cambridge, allows scientists to act with unprecedented precision against genes that affect a wide range of diseases, switching them on or off permanently.
The first drugs designed to target the genes have begun clinical trials in the United States on patients with arterial disease and diabetes-induced nerve damage. A third trial, for HIV, is due to begin within months. If they are successful, scientists predict that the technique could change the way many diseases are treated, making genetic therapies a routine part of medicine for the first time.
In some cases, the method will be used to switch off rogue genes that promote conditions such as heart failure or cancer. In others, it will help to activate genes that protect against nerve damage or encourage blood vessel growth.
In treating HIV, the aim is to modify T-cells from patients’ immune systems so that they become immune to infection with the virus. This would leave them with some working T-cells with which to fight off other infections, which are the chief cause of Aids deaths. The technique relies on a natural process by which the activity of genes is raised or lowered by proteins called transcription factors.
In 1985 Sir Aaron discovered a new class of proteins that mimic this function and can recognise specific stretches of DNA and bind to them, boosting the activity of genes or damping them down.
He named them zinc-finger proteins, after the metal that holds them together and the way in which they grasp DNA. Sangamo BioSciences, a company in California, has already developed several drugs based on the principle.
A zinc-finger protein specific to a gene is loaded with an enzyme called a nuclease, which will bind to the gene and turn it on or off. Sir Aaron told The Times: “We are taking nature’s own method of regulating gene activity and exploiting it for our own purposes. We can use this technique to change the function of a single gene permanently.
“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.”
Details of the technique are published today in the journal Proceedings of the National Academy of Sciences.
The most advanced of Sangamo’s drugs uses a zinc-finger nuclease to treat diabetic neuropathy, a common complication of diabetes that causes nerve damage and pain. The drug binds to a gene called VEGF-A, which is known to protect the nervous system, and switches it on to prevent nerve damage. Phase 2 trials of the drug are under way. The same gene is also being targeted to treat peripheral arterial disease which causes blocked arteries in the limbs. A zinc-finger drug that has started safety trials aims to stimulate VEGF-A activity, which can promote the growth of new arteries.
In the longer term, a similar approach might be used to grow new blood vessels in the heart, Sir Aaron said.
Sangamo is applying for regulatory permission to start testing a zinc-finger nuclease on HIV patients as well as developing drugs to treat glioblastoma, a type of brain cancer, and single-gene disorders such as sickle-cell anaemia.
timesonline.co.uk
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Also, from the BBC...
Gene targeting raises cure hopes
A more efficient way to shut down rogue genes raises hopes of new therapies for conditions like diabetes and HIV.
Systematically knocking out single genes potentially gives scientists unprecedented control over the processes which cause disease.
US and UK researchers have developed synthetic proteins which can target individual genes quickly, simply and with a high degree of success.
The study appears in Proceedings of the National Academy of Sciences.
The new technique is already being used in trials on a range of diseases.
The regulation of gene expression is controlled by regulatory proteins called transcription factors.
The researchers have created their own synthetic versions of these transcription factors called zinc-finger nucleases.
They can be used to cut into and inactivate a target gene in a very precise way, without affecting other nearby genes.
It is also possible to use a similar approach to activate beneficial genes by introducing new DNA at the point where the gene is cut.
Zinc-finger proteins were discovered and developed by Sir Aaron Klug, based at the Medical Research Council's Laboratory of Molecular Biology in Cambridge.
His work has been taken on by US firm Sangamo BioSciences.
Precision targeting
The targetting of individual genes is currently carried out using a process known as homologous recombination, which involves the exchange of genetic material between the target gene and DNA created in the lab.
However, this process is time consuming, can be very elaborate, requiring the insertion of markers into the target gene, and is not always very efficient.
Sir Aaron said: "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."
Animal trials are already under way to use the technique to knock out the receptor of HIV in immune system T-cells of patients with Aids.
If successful this will render the T-cells immune from HIV infection, and enable them to fight disease.
Clinical trials to aid patients with blocked blood vessels are also under way.
Dr Vincent Cunliffe, a genetics expert from the University of Sheffield, described the technique as "a powerful method for efficiently and selectively inactivating" individual genes.
He said: "This technology will have many applications in future research."
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