By: QUINN EASTMAN - Staff Writer

A new way to selectively turn off genes has taken the biology laboratory by
storm in the last few years. The increasingly popular technique, called RNA
interference, helps scientists to probe the function of a gene and could
potentially be used to treat a variety of diseases.

RNA interference resembles antisense, a technique that Carlsbad-based Isis
Pharmaceuticals has painstakingly developed since its founding in 1989.
Antisense uses synthetic bits of genetic material to block the function of a
specific gene inside the body.

In principle, antisense could be used against inherited diseases, chronic
conditions such as heart disease or autoimmune disorders, or even viruses
such as hard-to-treat hepatitis B or C. In the case of an inherited disease
such as Huntington's or Lou Gehrig's, the target would be the faulty copy of
the gene to blame.


Scientists would just need to figure out which of the human body's 30,000
genes to home in on, and how to get the antisense drugs into the right
cells ---- two daunting tasks.

Despite exciting investors and attracting millions of research dollars
during the last two decades, antisense technology has produced just one
FDA-approved drug, Vitravene, sold by Isis and injected in the eye to combat
an AIDS-related viral infection.

"I think everyone believes (RNA interference) has incredible potential,"
said Mark Kay, a pediatrician and geneticist at Stanford University, who is
studying ways to use RNA interference to fight hepatitis viruses.

"Compared with previous antisense techniques, there's no doubt that this is
the most effective," he said. "But we need to move forward very cautiously."

Yet momentum is building behind research on using RNA interference as a
therapeutic technique. Researchers at one of Isis' partners, Alnylam
Pharmaceuticals in Massachusetts, demonstrated recently in the journal
Nature that they could lower cholesterol in mice by using an RNA
interference-based treatment.

The first clinical trial that uses an RNA interference-based drug began in
October. Philadelphia-based Acuity Pharmaceuticals is aiming to treat
macular degeneration, a major cause of adult blindness.

But many researchers say there are still significant barriers to wider use
of RNA interference clinically, rather than in university and industry labs,
where the technique has had most of its success so far.

How it works

RNA acts as the messenger between DNA, the material of the genetic code, and
proteins, the tools that do the work of the cell. Each gene can be read out
into an RNA message to make a specific protein, but not every gene gets
turned on in a given cell.

Both antisense and RNA interference cause messenger RNA to get chewed up by
proteins in the cell, preventing the message from being acted upon.

Antisense uses DNA that reads like the complement ---- or antisense ---- of
the targeted message and binds to it. The RNA-DNA hybrid structure gets
recognized by a special enzyme that eats it up.

RNA interference is really an extension of antisense, said Frank Bennett,
vice president of antisense research at Isis. The difference is that RNA
interference uses double-stranded RNA, or part of a gene read into RNA and
its complement stuck together in the same molecule.

RNA interference appears to be more potent than previous versions of
antisense because it hijacks some of the cell's internal regulatory
machinery that determines whether genes get turned on or off. This special
potency was discovered in 1998 by scientists at the Carnegie Institution of
Washington working on worms, but it works in plants, fruit flies and humans,
as well.

The machines that RNA interference take over appear to be part of an ancient
evolutionary defense mechanism against viruses, whose perverted genes
sometimes come in a double-stranded RNA form.

"It's part of how creatures learned to resist viruses before there ever was
an immune system with antibodies," said Mario Stevenson, a virologist at
University of Massachusetts Medical School.

There are hints that RNA interference machinery still has an anti-viral
function because influenza virus, for example, tries to knock it out when it
invades cells, he said.

Big business ---- in the lab

RNA interference quickly gained popularity among university biologists who
wanted a way to shut off specific genes. In 2002, it was proclaimed
"Breakthrough of the Year" by Science magazine.

Carlsbad-based Invitrogen, which sells tools to biology researchers, has
jumped into the field in a big way, becoming one of the leading suppliers of
RNA interference products.

"In the past year, it's really gained acceptance as a standard method in the
lab," said Marilyn Datta, vice president of RNAi for Invitrogen. The
earliest adopters of the technique were university scientists, but an
increasing number of industrial researchers are using it, she said.

Invitrogen can make synthetic RNA for scientists to use on cells growing in
dishes, as well as more elaborate tools for introducing RNA interference
agents into animals.

Consulting firm Frost & Sullivan predicted this year that RNA interference
sales revenues will grow by 30 percent a year, growing to $328 million in
2010 from around $48 million in 2003.

The largest part of that money would come from pharmaceutical firms using
RNA interference for "target validation," the firm projected. Target
validation means figuring out whether a potential drug a company's
scientists are studying will turn genes on and off in the way they want.

Some venture capital firms such as Boston's Oxford Bioscience have invested
in start-up companies that use RNA interference, such as Alnylam and Sirna
Therapeutics in Colorado. But Forward Ventures, San Diego's premier biotech
venture capital firm, has stayed clear so far.

"It's too soon," said Ivor Royston, a partner at Forward Ventures. "I don't
think the current RNA interference companies are going to generate viable
products soon enough to reward our investors."

Barriers to clinical use

Antisense and RNA interference both face similar obstacles before they can
be effective ways to fight disease.

"It's all about delivery," said Stevenson with the University of
Massachusetts.

It's no coincidence that the first RNA interference drug tested in a
clinical trial gets injected into the eye, the same site of action of the
first antisense drug, he said.

"It's the easiest place to go; the delivery problems aren't there because
you're delivering the RNA to a specific place," he said.

The authors of Alnylam's recent Nature paper used a clever trick by
chemically attaching the RNA to a molecule of cholesterol, which gets taken
up by the liver.

"It's frustrating," he said. "Most of any RNA agent gets taken up by the
liver, anyway."

Stevenson is working on using RNA interference to fight HIV; in his case,
the task is to deliver a drug specifically to the lymph node.

In addition to the specificity problem, unprotected RNA lasts only minutes
in the blood because enzymes break it down. In high quantities,
double-stranded RNA also can activate a general anti-viral defense system
called the interferon response.

Isis has spent years developing chemical modifications that protect RNA from
the body's enzymes, Frank Bennett said. The modifications even enhance the
inhibitory effects, he said.

Other companies, such as Rosetta Inpharmatics in Seattle, have also detected
glitches where RNA interference can shut off genes that are similar to, but
not the same as, the target gene.

"It will take some time and effort to overcome the hurdles," Bennett said.
"But we're making a bet that it will be an exciting area in the future."

Contact staff writer Quinn Eastman at (760) 740-5412 or
qeastman@....

Susie

Email: angelrose@...
Home Page: http://www.geocities.com/susie_que_56/angelwhispers51.htm
Yahoo Group: http://groups.yahoo.com/group/huntingtonsatrisk/
Yahoo ID: susie_que_56
AIM: susiemayhem

A Friend Is One Who Comes In When The Whole World Has Gone Out
Cure Huntington's Disease



--
No virus found in this outgoing message.
Checked by AVG Anti-Virus.
Version: 7.0.298 / Virus Database: 265.6.7 - Release Date: 12/30/2004