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RNA therapy against three brain diseases

Monday, May 26, 2003
United Press International
Reported by Charles Choi, UPI Science News, in New York
Iowa City, Iowa

A new but still experimental therapy has neutralized Lou Gehrig's disease and two other brain-scrambling disorders in lab-grown human cells, two teams of scientists have discovered.

Medical experts said this advance reveals how potentially revolutionary the new genetic technique known as RNA interference could be against such major diseases as Alzheimer's and Parkinson's, and perhaps even cancer and AIDS.

"As a neurologist who sees people suffering from these devastating illnesses, I consider it a major impact if we could target these incurable diseases," Henry Paulson, the first team's lead researcher and a neuroscientist at the University of Iowa, told United Press International.

Paulson's team, reporting this week in the Proceedings of the National Academy of Sciences, found small RNA molecules could silence mutant genes linked with two other brain diseases: Machado-Joseph disease, also known as spinocerebellar ataxia type 3, which leads to increasing weakness and clumsiness, and a complex condition known as frontal-temporal dementia with Parkinsonism, which is very much like Alzheimer's.

RNA interference was discovered some five years ago in plants and worms. Since then, it already has developed into "a multi-million-dollar market for the biotech industry," said biochemist Philip Zamore at the University of Massachusetts Medical School in Worcester, member of the second team.

In findings appearing in the journal Aging Cell, Zamore and colleagues used RNA interference to neutralize a mutant gene responsible for Lou Gehrig's disease, or amyotrophic lateral sclerosis (ALS).

"This is a disease that attacks the muscles and nerves and causes them to die. The patient develops paralysis and eventually dies of respiratory failure," said Zamore's partner, neuroscientist Zuoshang Xu. "Usually, after diagnosis, the patients live for one to five years. At this point, there is no treatment."

Like DNA, RNA molecules are made of strings of components known as nucleotides. RNA ferries instructions coded in DNA to the body's cellular machinery.

In worms, the scientists discovered unexpectedly that injected RNA could interfere with its messenger brethren, thus preventing the assembly of corresponding proteins. They theorize this mechanism likely is an ancient defense system that evolved very early in both plants and animals to stifle foreign genes from viruses.

Instead of using chemicals to attack proteins from a target gene -- which inadvertently could disable vital look-alikes -- RNA injection can silence a specific gene.

"Instead of trying to find a protein they can target, this just stops the protein from being made in the first place," psychologist Nancy Wexler, president of the Hereditary Disease Foundation in Santa Monica, Calif., told UPI. "It's infinitely more powerful. It's getting at the root of the problem -- the soul of the matter. They're going to the source of the Nile and fixing the problem that's wiping out fields and drowning people, instead of trying to build a dam hundreds of miles downstream in the muddy flood delta plains. Bravo to them, I say!"

Other researchers point out RNA interference techniques seem ideal to combat diseases that are caused by mutant genes.

"We get one set of genes from our mother and one set from our father," molecular biologist Kenneth Kosik at the Harvard Institutes of Medicine in Boston explained. "What the researchers have done is develop a way to suppress just the abnormal gene but keep the normal gene going." Silencing the normal version of the gene could prove lethal, if that protein normally plays a vital role.

"The difference between the mutant gene and the normal is only a single nucleotide," he explained. "There are 3 billion nucleotides. They've developed a technique to actually separate a single error out of 3 billion. And that's very, very elegant," Kosik, who did not participate in either study, told UPI. "It's going to, in my view, revolutionize the way we practice medicine."

Silencing the genes behind a cancer cell's out-of-control behavior could kill them, Zamore said. Given RNA interference apparently evolved to stop viruses, scientists also think it could be deployed against HIV and other as-yet incurable diseases.

"These pioneers prove that a general strategy can be applicable for the manipulation of a single gene, for everything to Huntington's, Lou Gehrig's, Alzheimer's, Parkinson's, cancer. These demonstrations of the power and success of this approach will change medicine and genetics almost immediately, because people will be able to target the abnormal genes themselves selectively and shut them off, sparing the healthy genes," Wexler told UPI.

The challenge remains to bring RNA interference from lab-grown human cells to attacking disease in the brain. Paulson and his team are working on animal targets. Zamore and his team have already registered success against livers in mice, although he admits that's a long way from nerves.

"Direct injection into the brain is something that is not something we would do readily," Kosik said. "But if someone has a serious, life-threatening disease and there is potential for treatment by injection, even into the brain, I think this option becomes more realistic."

Injected RNAs could remain potent for weeks to months, "maybe even longer," Kosik suggested. Paulson is also working on weaving genes for interfering RNAs into diseased cells by using viruses, for a one-time delivery.

"There are still some obstacles along the way. But these findings have taken us one more step towards making RNA interference therapeutics a reality," Kosik said.

"Clearly when you get to diseases like Alzheimer's and Parkinson's, you're talking about a significant proportion of the population. If this works in a safe and effective way, that could be a big market, and an important thing to do," neurologist Kenneth Fischbeck at the National Institute of Neurological Disorders and Stroke in Bethesda, Md., told UPI.

Copyright © 2003 by United Press International