New technique for 'switching off' genes could end fatal brain diseases

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Incurable brain disorders, such as Huntingdon's disease, could soon be treated using a revolutionary technique for "switching off" disease genes.

Incurable brain disorders, such as Huntingdon's disease, could soon be treated using a revolutionary technique for "switching off" disease genes.

In a groundbreaking study, scientists have shown for the first time that it is possible to stop a progressive brain disease in mice with a genetic technique known as RNA interference (RNAi).

The research raises the possibility of using the method to treat degenerative brain conditions such as Alzheimer's. Specialists in Huntington's ­ a fatal inherited disease that strikes in middle age ­ are particularly excited with the results.

The latest research was carried out by a team led by Beverly Davidson of the University of Iowa who used RNAi to correct a genetic defect in mice suffering from a progressive brain disorder similar to Huntington's disease in humans.

Mice with the inherited defect who were given the RNAi treatment did not develop the symptoms seen in untreated mice. Nor did the treated mice show any signs of suffering from toxic side-effects, indicating that the technique is safe.

Dr Davidson said that the findings, published in this month's Nature Medicine, were among the most important results of her career because they demonstrated the possibility of directly attacking the faulty gene responsible for Huntington's disease. "I'm extremely excited about the potential of RNAi and cautiously optimistic about its possible use in human medicine," Dr Davidson said.

RNAi works by shutting down or "silencing" a disease gene while leaving other healthy genes untouched. This makes it perfect for treating Huntington's disease, a "dominant" genetic defect caused by a single defective version of a gene that people inherit as two copies, one from each parent.

Conventional gene therapy, which attempts to add a healthy version of a gene that is missing or defective in a patient, would not work for Huntington's because in this disease it is necessary to stop the defective version of the gene from causing a build-up of toxic proteins in the brain. The RNAi process used by the Iowa team specifically targeted the defective Huntington's gene by silencing it, leaving the healthy version of the same gene to carry out its vital duties.

"This is the first example of targeted gene silencing of a disease gene in the brains of live animals and it suggests that this approach may eventually be useful for human therapies," Dr Davidson said. "We have had success in tissue culture, but translating those ideas to animal models of disease has been a barrier. We seem to have broken through that barrier," she said.

Nancy Wexler of Columbia University in New York, a world authority on Huntington's disease, said RNAi offers the most promising potential treatment for the disease she has seen. "When I first heard of this work, it just took my breath away. Its everything you ever wanted to hear and more," said Professor Wexler, president of the Hereditary Disease Foundation in New York and a member of the team that originally discovered the Huntington's gene.

Phillip Sharp, a Nobel laureate from the Massachusetts Institute of Technology in Boston, said Dr Davidson's findings were "striking" because they demonstrated that RNAi may work for human patients suffering from a range of debilitating brain diseases. "It shows that, in the context of the biology, it's possible to do. This is a significant step, there's no doubt about it," Professor Sharp said.

Dr Davidson said further animal research would be necessary to show that the technique was safe and effective before it could be used on humans.

The first clinical trials on Huntington's patients, or people with related brain disorders, are likely to begin within the next five years provided there are no signs that the technique is dangerous in humans.

Huntington's disease is a good candidate for RNAi treatment because a genetic test already exists to see who has inherited the condition. Secondly, treatment could begin long before the onset of the first symptoms. The disease affects 1 in 10,000 people. Patients suffer severe physical and psychological degeneration.


The breakthrough that could lead to cures for inherited brain disorders such as Huntington's is known as RNA interference, a phenomenon that has generated huge interest since was first discovered in 1998.

RNAi is a way of switching off or "silencing" a single harmful gene without affecting the many thousands of other vital genes. The applications range from switching off the genes of invading viruses to silencing the cancer-causing genes of tumours. Now, RNAi has also proved it has a future in treating diseases caused by inherited defects in single genes.

In 1998, Andrew Fire, of the Carnegie Institution in Baltimore, found in studies on the tiny nematode worm that molecules of RNA, which carry genetic information, could be tailored to switch off certain genes. In a seminal paper published in the journal Nature he and his colleague Craig Mello coined the phrase "RNA interference".

Further work showed that the interference principal appeared to be universal to other more complex animals, and, crucially, in human cells that could in the test tube be given immunity to invading viruses such as HIV and polio.

The big question was whether this ability to silence genes could be "delivered" to all the cells of the body that needed it. Beverly Davidson's work shows that in a mammal the delivery of RNAi can work, even across the notoriously difficult biological barrier that protects the brain. She used a harmless carrier vehicle called adeno-associated virus to take the RNAi molecule into the diseased cells of the brain where the defective Huntington gene needed to be silenced. It worked.

Phillip Sharp, a Nobel laureate at the Massachusetts Institute of Technology, said that the work has shown for the first time that RNAi can be used to treat a disease in an animal.

"The broader science of RNAi is spectacular. Its just absolutely spectacular," Professor Sharp said.

"This is not hype. The biggest science prizes in the world will fall to RNAi."