Gene genius: Are scientists closing in on the holy grail?

Imagine a treatment for cancer, a cure for infectious diseases such as Aids, or maybe an effective therapy for blindness or a lethal brain disease. Now imagine that one breakthrough is responsible for all this medical hope.

The breakthrough is RNA interference (RNAi), which some scientists believe could be the biggest advance in healthcare since the development of antibiotics. There is barely an area of medicine that may not be touched by future advances in RNAi - a technique for switching off genes selectively and precisely.

RNAi was only formally recognised in 1998 but over the past few years it has emerged as one of the hottest developments in the field of medical science. Yet another international conference on RNAi (titled RNAi Europe) is planned at the end of September in Prague.

The sheer range of illnesses and disorders that RNAi might address is unprecedented. RNAi promises to become a radically new form of treatment for an entire spectrum of illnesses, whether they result from an infectious attack from the outside environment or an inner malfunction of the body's vital genes.

In 2002, the journal Science voted RNAi its top breakthrough of the year and biotechnology companies are pumping millions into its development. But sceptics have warned that medical science is littered with false dawns. RNAi, they warn, might fails the ultimate clinical tests of safety and efficacy.

RNA stands for ribonucleic acid, the less well known cousin of deoxyribonucleic acid (DNA), the molecule of inheritance. RNAi works by interfering with the normal activity of genes. Scientists - to their amazement - discovered that short molecules of RNA can block or "silence" the activity of a particular gene, working like the dimmer switch of an electric light. RNAi lowers or halts the production of the proteins produced from the genes on the DNA of a chromosome. Scientists were surprised to discover that RNAi seems to be a universal mechanism used by all living organisms for controlling gene activity.

Everything from petunia plants and fungi to fruit flies, nematode worms and mice use RNAi to switch off their genes. Four years ago, scientists found that human cells also use RNAi. It may have evolved as a protection against viruses by targeting and switching off vital viral genes - a sort of micro immune system.

Discovering that RNAi works inside human cells led to the idea of exploiting the phenomenon therapeutically. Could potentially harmful genes - either the body's own mutations or viral invaders - be switched off using RNAi itself? If so, virologists could design a new type of anti-viral drug that cripples the ability of an infectious agent to attack human cells. Cancer specialists could develop RNAi as a therapy to switch off the genes of a cancer cell, forcing it to commit suicide while leaving healthy, cells unaffected. Meanwhile, geneticists believed they might be able to rid the body of the harmful mutations behind many inherited disorders.

Many scientists were ecstatic about the prospect for treating human diseases. "The broader science of RNAi is spectacular," Professor Phillip Sharp, a Nobel laureate at the Massachusetts Institute of Technology, said in 2003.

Three years later, Professor Sharp remains in ebullient mood. "The advances in the field have exceeded expectations," he says.

The most advanced clinical trials of RNAi are being carried out in America by two biotechnology companies, Acuity and Sirna. Both involve patients suffering from macular degeneration, when the abnormal growth of blood vessels in the eye causes visual impairment and, eventually, blindness.

Both companies have developed RNAi therapies that target the human gene that makes a protein called vascular endothelial growth factor. This growth factor stimulates the growth of the blood vessels that cause the disorder. The aim of the RNAi therapy is to silence this gene, curbing the further invasion of blood vessels.

Scientists believe that macular degeneration is a good disorder to test RNAi because the eye is a relatively closed system easily treated with direct injections. Acuity has already completed phase I clinical trials, which test for toxicity and general tolerance, and is preparing for larger, phase-II clinical trials.

A spokesman for Acuity said that results of the phase-II trial are expected soon. But it is only after the much larger phase-III clinical trials - involving hundreds or possibly thousands of patients - that doctors will be able to say whether RNAi is any good for macular degeneration.

One of the beauties of the RNAi approach is that it is comparatively easy for scientists to make RNAi drugs. Effectively they are just small strands of the RNA molecule, which can be synthesised by machine. Each strand is about 22 units long - tiny compared with the 3 billion units that make up the entire DNA molecule of the human genome.

Each of these "short-interfering" strands of RNA can be targeted to work against a particular gene, which is one of the reasons why the technique is so attractive. There is less chance of cross-reactions or unintended side effects. However, one of the biggest problems with RNAi is "delivery": how do you make sure that the synthetic RNA molecules get inside the cells that matter?

Professor Beverly Davidson of the University of Iowa is using a specially adapted virus to do the job. She is developing a technique of "infecting" certain parts of the brain with an "adeno-associated" virus. This is genetically modified to carry RNAi molecules into the brain. These are targeted to silence the mutated gene responsible for Huntington's disease - an inherited condition that leads to an appalling degeneration of the brain.

Huntington's disease is a good target for RNAi therapy because it is a "dominant" genetic disorder - just one copy of the defective gene results in the disease. Conventional gene therapy, which attempts to add a healthy version of a gene that is missing or defective, would not work for Huntington's. In dominant genetic diseases it is necessary to stop the mutant version of the gene from working.

Professor Davidson's group is instead targeting the defective copy of the gene, leaving the healthy version unaffected, so permitting it to carry out its normal duties. Tests on a mouse model of Huntington's have been successful. Treated animals did not develop symptoms of the disease, whereas untreated mice went on to suffer. Nor did the treated mice suffer any apparent ill effects, leading some commentators to say that it was arguably one of the most promising therapies for this crippling disease.

"This is the first example of targeting 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," Professor Davidson said when the results were announced.

Today, Professor Davidson remains cautiously optimistic, aware that hype is not in the best interests of patients and their families. "RNAi is extremely exciting," she says. "Scientists are continuing to unravel how it works and investigations are finding uses for RNA. Therapeutic use of RNAi has much potential, but like everything, there will be hurdles to discover, and to find a way over or around," she says.

A range of infectious diseases caused by viruses are also being studied with a view to being treated with some kind of RNAi therapy. Alnylam Pharmaceuticals has, for instance, applied for a drug licence to start clinical trials of its proprietary product for the treatment of respiratory syncytial virus, a major cause of breathing illnesses in young children, the elderly and immune-deficient patients.

The Alnylam drug is designed to silence a gene that is essential for the virus's replication. Tests on animals, where the drug was administered as a nasal spray, have shown that it can prevent infection with the virus without any toxic side-effects, the company says. The hope is that it could prevent infection with a virus that is known to increase the risk of children developing asthma in later life.

Alnylam is also experimenting with a way of reducing blood cholesterol levels using RNAi, which paradoxically was attached to cholesterol molecules as a way of delivering it. The RNAi was targeted to silence apolipoprotein B, a regulator of cholesterol metabolism. The company admitted that it was an experiment that seemed unlikely, but tests on mice showed that it worked and now the firm wants to try it out on people.

John Rossi of the City of Hope Beckman Research Institute in Duarte, California, says that this study showed that it may be possible to treat people systemically with RNAi. "This is the first published demonstration that you can systemically inject RNA and have them taken up by cells in several different tissues," Professor Rossi says.

The delivery technique that he is working on relies on taking blood stem cells from the bone marrow of an Aids patient, infecting these cells with RNAi molecules targeted against a vital gene used by the Aids virus, and then reinjecting these cells back into the patient. The hope is that the cells will develop into mature immune cells that produce RNAi molecules that prevent HIV replication.

"Our HIV trial is well on its way to initiating this year," Professor Rossi says. One of the issues he has had to address, however, is how to make sure that the virus he uses to infect the patient's cells with RNAi molecules is itself safe. He intends to apply for a clinical trials licence this year.

In Britain, scientists are also excited about RNAi. Jo Milner, a cancer researcher at York University, is developing the technique to silence the genes that are implicated in triggering colon cancer, with some success in test-tube studies. "It is by far one of the most exciting discoveries in biology," Dr Milner says. "It is a natural process and has opened our minds to a whole new dimension of molecular and cellular biology."