A couple of years ago, Science
was hailing RNA interference (RNAi), capable of switching
off disease-causing genes, as the "breakthrough of the
year." Now, two years later, we're about to find out whether
the light switch gene can live up to all the hype.
Amidst a flurry of expectations,
the FDA recently approved an application from Philadelphia-based
Acuity Pharmaceuticals to begin the first clinical trials
of RNAi. Starting this month, at Dr Lawrence J Singerman's
retinal clinic in Cleveland, OH, preliminary trials
will treat patients suffering from the "wet" form of
age-related macular degeneration (ARMD), a degenerative
retinal disease that is the leading cause of blindness
in Canada. Acuity have secured $15 million US to fund
the research.
In RNAi, a single strand of RNA
is duplicated so that it becomes a double strand called
dsRNA. In 1998 American researchers Drs Andrew Z Fire
and Craig Mello experimented by injecting dsRNA into
cells in roundworms. They found that if the cell recognizes
the two-timing RNA (which should be single-stranded),
it leaps to the attack and destroys it. But most importantly,
the intruding dsRNA isn't the only target. Any other
RNA in the cell with the same genetic sequence as the
dsRNA becomes interpreted as a renegade and gets zapped
as well.
With careful construction of the
appropriate dsRNA, scientists believe they can selectively
stop disease-causing genes from being expressed. In
other words, any destructive proteins produced by the
target gene simply won't survive.
GENE
SILENCER
The reason why the cell seeks out and destroys RNA strands
after detecting the presence of dsRNA may be a form
of cellular resistance to certain viruses that have
dsRNA. Thanks to this naturally occurring defense mechanism,
RNAi researchers may have found an effective and relatively
inexpensive way of isolating and silencing the expression
of individual genes.
Patients at Dr Singerman's clinic
with the "wet" form of ARMD will be administered injections
of dsRNA into the whites of their eyes. The researchers
hope that by turning off the RNA, which codes for the
proteins responsible for producing the characteristic
leaky excess blood vessels in ARMD, the problem will
be thwarted at the source.
Hopes are high that RNAi will open
up a whole new armamentarium against a wide array of
illnesses ranging from Huntington's, Parkinson's and
Lou Gehrig's disease to AIDS, hepatitis and cancer.
But after similar hopes were dashed by the failures
of two other once-lauded gene-zappers � antisense and
ribozymes � scientists and venture capitalists alike
will be keeping their eyes trained on those trial results
trickling out of Cleveland.
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