Advances in gene therapy

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RNA therapy against three brain diseases

United Press International

Monday, May 26, 2003

IOWA CITY, Iowa, May 26, 2003 (United Press

International via COMTEX) -- 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

son, the first team's lead researcher and a

neuroscientist at the University of Iowa, told United

Press International.

son'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-ph 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 Wexler, president of

the Hereditary Disease Foundation in Santa ,

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 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. son 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. son 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 Fischbeck

at the National Institute of Neurological Disorders

and Stroke in Bethesda, Md., told UPI.

--

(Reported by Choi, UPI Science News, in New

York)

Copyright 2003 by United Press International.