Gene therapy gives hope to brain disease sufferers

By STEVE CONNOR

Fatal brain diseases once considered to be incurable could soon be treated using a revolutionary technique that has effectively triggered a recovery from a similar disorder in laboratory animals.

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 is important because it raises the possibility of using the method to treat degenerative brain conditions such as Huntington's disease and 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 which 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 the findings, published in 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 normal duties that are vital to life.

"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."

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 had seen so far.

"When I first heard of this work, it just took my breath away," said Professor Wexler, president of the Hereditary Disease Foundation and one 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 might 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 is about to finish another study on mice that appears to support her earlier findings. Further animal research was necessary to show that the technique was safe and effective before it could be used on humans, she said.

The first clinical trials on Huntington's patients, or people with related brain disorders, could begin within the next five years.

Huntington's disease is a good candidate for RNAi because a test already exists to see who has inherited the condition. Secondly, treatment could begin before the onset of the first symptoms, which strike between the ages of 30 and 50.

- INDEPENDENT