[Homestead] New medical direction, turn off bad genes

Tvoivozhd tvoivozd at infionline.net
Tue Sep 14 11:02:52 EDT 2004

tvoivozhd---may not work, but sure as hell is worth trying.

The New York Times

          September 14, 2004

    Method to Turn Off Bad Genes Is Set for Tests on Human Eyes


If all goes according to plan, about half a dozen elderly people at risk 
of blindness will visit Dr. Lawrence J. Singerman's retina clinic in the 
coming weeks to receive injections in the whites of their eyes.

The experimental injections will contain a new type of drug based on a 
recently discovered genetic phenomenon, called RNA interference, that 
has excited scientists with its versatile and powerful ability to turn 
off genes. Having quickly become a standard tool for genetic studies in 
the laboratory, the technique is now set to be tested in people for the 
first time.

Acuity Pharmaceuticals, a two-year-old company in Philadelphia, said 
last week that the Food and Drug Administration had granted permission 
for it to conduct the first human test of RNA interference - the 
experiment in which Dr. Singerman's clinic in Cleveland and a second 
clinic plan to participate. The early-stage clinical trial, largely a 
safety review, will test the technique against the gene that sets off 
the process of age-related macular degeneration, a deterioration of the 
retina that is the leading cause of blindness in the elderly.

Success is far from guaranteed. While RNAi, as it is known, works well 
in the laboratory, there are questions about whether it will work in 
people. Two other techniques that were also once considered highly 
promising ways to turn off genes - antisense and ribozymes - have not 
yielded any significant drugs despite years of effort.

But if it works, RNAi could potentially yield a cornucopia of other 
drugs designed to silence errant, disease-causing genes in the body, or 
disarm an invading virus by knocking out its genes. A second company, 
Sirna Therapeutics 
of Boulder, Colo., applied to the F.D.A. last week for permission to 
begin a trial of its own drug for macular degeneration.

Several other small biotechnology companies say they, too, are planning 
clinical trials in the next couple of years to use RNA interference to 
treat that disease and others including AIDS, hepatitis, Parkinson's and 
Lou Gehrig's disease. It could become one of the quickest ways that the 
new knowledge about human genes generated by the Human Genome Project is 
translated into medical benefits.

"From the basic science that's been done in this area, I think the 
direction has great promise," said Dr. Singerman, president of Retina 
Associates of Cleveland. Noting that the small Acuity trial will have 
only a few investigators, he added, "I kind of feel privileged to be one 
of them."

Big pharmaceutical companies, which already use RNAi as a laboratory 
technique for testing how suppressing a single gene affects a cell, are 
joining the field by linking up with smaller RNAi-specialist companies. 
formed a partnership with Alnylam Pharmaceuticals to work on drugs for 
eye diseases, and Eli Lilly & Company signed a deal with Sirna 
Therapeutics to explore RNAi drugs for cancer.

Like the older gene-intervention techniques, the RNAi approach involves 
taking a short stretch of RNA, the cousin of the DNA in genes, and 
delivering it into cells in the body. But delivery has not proved an 
easy task. RNA is quickly chewed up by enzymes in the blood or removed 
by the liver and kidneys and excreted. And even if the RNA survives its 
journey through the bloodstream, it cannot easily pass through the 
membranes surrounding the cells in which it is needed.

"There's not a lot of evidence showing it can just be injected in blood 
and work," said David R. Corey, professor of pharmacology at the 
University of Texas Southwestern Medical Center at Dallas.

Backers, though, say that RNAi appears to be more potent than the 
earlier techniques because it makes use of the cell's natural mechanism.

"There's no doubt in my mind that this is the clear winner," said Mark 
A. Kay, a Stanford professor. He hopes to test an RNAi treatment for 
hepatitis C in cooperation with Benitec, an Australian company that now 
owns a company he founded.

Some animal tests have demonstrated the technique's potential. According 
to a paper published in June, scientists at the F.D.A. led by Suzanne L. 
Epstein used RNAi to partly protect mice from lethal flu viruses, 
including two strains of avian flu that experts worry could become the 
basis for a new pandemic.

Beverly L. Davidson and colleagues at the University of Iowa reduced the 
severity in mice of one type of ataxia, a hereditary brain disease 
somewhat similar to Huntington's. "It's very exciting,'' she said, 
"because we finally have a tool to approach therapies" for diseases like 
Huntington's and ataxia.

But the animal tests have not been numerous. And in some cases, to 
overcome the delivery obstacles, the RNA was injected into the mice at 
such high pressure and volume that some experienced temporary heart 
failure. It is not yet known whether injections of lower volumes of 
fluid at lower pressures, as required for human safety, will be effective.

RNA is a string of chemical units, called bases, that represent the 
letters of the genetic code. It serves as a messenger, carrying the 
recipe for a protein from the DNA in the genes to the cell's 
protein-making machinery. Proteins form much of the structure of a cell 
and carry out much of its activities.

While DNA has two strands - the famous double helix - RNA is usually 
single-stranded. If cells sense double-stranded RNA, they act to destroy 
it and any other RNA with the same sequence. Some researchers conjecture 
that this RNA interference mechanism might have evolved as a defense 
against viruses, which sometimes create double-stranded RNA.

Scientists can harness this mechanism to prevent any gene in the body 
from being used to make a protein, effectively shutting off the gene. 
They synthesize a short string of double-stranded RNA that corresponds 
to part of the messenger RNA carrying the protein recipe. Rather than 
creating the protein, the cell destroys the messenger.

The process is straightforward enough that drugs using this mechanism 
are being readied for clinical trials only three years after RNAi was 
reported to work in the cells of mammals. "It has had a remarkably fast 
transition to the clinic," said Andrew Z. Fire, a professor at Stanford 
who was a co-discoverer of an animal form of RNAi in a worm around 1998.

Several of the first tests of RNAi will be for the "wet" form of macular 
degeneration, in which abnormal leaky blood vessels damage the retina. 
This disease was chosen partly because the RNA can be injected directly 
into the eye, easing the delivery challenge.

Other companies have demonstrated that the disease can be treated by 
blocking the action of a protein called vascular endothelial growth 
factor, which spurs blood vessels to form and to leak. But instead of 
blocking the action of the protein, the RNAi approach, by turning off 
the gene, would block the protein from being formed in the first place.

"The other technologies really act like a mop in a leaky basement," said 
Samuel J. Reich, the senior director of research and development at 
Acuity. RNAi, he said, "turns off the leak at the faucet."

Acuity, which plans to begin its human trials next month once it 
receives approval from a review board for the clinics, has gained a head 
start on its two closest competitors, Sirna and Alnylam, by taking the 
simpler approach of using a plain double-stranded piece of RNA. Its 
rivals are both chemically modifying their double-stranded RNA in an 
effort to make their treatments more effective and longer-lasting, 
cutting down on the number of injections patients would need.

"You can't simply take a naked short interfering RNA and use it as a 
drug," said John Maraganore, chief executive of Alnylam, deriding 
Acuity's approach.

Mr. Reich countered that modifying the RNA, as his competitors plan to 
do, might increase the side effects.

Alnylam, which is based in Cambridge, Mass., and was founded in 2002 by 
some academic pioneers of RNA interference, hopes to begin a trial 
treatment for macular degeneration in the second half of next year. It 
is also working on a treatment for Parkinson's disease in which the RNA 
would be injected directly into the brain.

Sirna, besides its work in macular degeneration, is pursuing a treatment 
for hepatitis C and has licensed the work done at the University of Iowa 
to treat Huntington's disease.

Another company, CytRx 
of Los Angeles, hopes to begin a trial next year to treat a form of Lou 
Gehrig's disease that is caused by a gene mutation. It is also working 
on drugs for obesity and diabetes. Two other companies, Benitec and 
Nucleonics, have chosen not to try using short pieces of RNA as drugs. 
Instead, they create genes that cause the body to produce RNA that folds 
back on itself like a hairpin, producing a double strand.

Having the body make its own interfering RNA could eliminate the need 
for frequent injections, although delivering genes into cells - known as 
gene therapy - is a field with its own failures and safety concerns.

Benitec is working with the City of Hope National Medical Center in 
Duarte, Calif., on plans for beginning tests next year of RNA 
interference as a treatment for H.I.V., the virus that causes AIDS.

John J. Rossi, a scientist at City of Hope, said patients would first 
have their immune systems wiped out by chemotherapy and then receive a 
transplant of their own bone marrow stem cells. But before the 
transplant, the stem cells would be given a gene to make double-stranded 
RNA that corresponds to a gene in H.I.V. The idea is to repopulate the 
immune system with cells that will fend off re-infection by H.I.V.

To be eligible for the trial the patients must also have lymphoma, a 
cancer that can be treated by bone marrow transplantation - an arduous 
and risky procedure that would not normally be used on patients with 
H.I.V., Dr. Rossi said.

The other company taking the folded RNA approach, Nucleonics, a 
privately held company in Horsham, Pa., hopes to begin a trial to treat 
hepatitis B by the end of next year, according to its chief executive, 
Robert J. Towarnicki.

Numerous uncertainties remain about whether the drugs can be safe and 
effective. RNAi, for example, might not completely repress a 
disease-causing gene, making a drug ineffective. Some studies, 
meanwhile, have shown that the RNA can reduce the activity of genes 
other than the intended one, possibly genes that partly match the 
sequence of the target. Such inaccuracies could lead to undesirable side 
effects in the patient. Double-stranded RNA can also provoke a powerful 
immune response in some situations.

Natasha J. Caplen, a gene therapy expert at the National Cancer 
Institute, said the F.D.A. had not decided how it would regulate RNAi 
drugs, making it unlikely that the companies would be able to begin 
clinical trials as quickly as they hoped. The F.D.A., which as a matter 
of policy declined to verify whether it had granted Acuity permission to 
begin its trial, said that for now it would consider each request on its 

Besides scientific and regulatory issues, the field is facing possible 
legal battles for control of crucial patents, and also the challenge of 
attracting investors. Sirna's stock traded as high as $8 last November 
but closed yesterday at $2.81. Alnylam, which went public in May, was 
forced by a lukewarm market response to reduce the price of the stock 
offering to $6 a share, down from the hoped-for $10 to $12. The stock 
closed yesterday at $5.82.

"This is a new technology and there are reasons for people to be 
skeptical until there's proof points out there," said Dr. Maraganore of 

Acuity, for its part, hopes the first proof points might soon be in the 
eyes of Dr. Singerman's beholders.

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