8-Humans: Controversy over gene therapy 'breakthrough'
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-------------------------------- GENET-news -------------------------------
TITLE: Controversy over Gene Therapy 'Breakthrough'
SOURCE: The Institute of Science in Society, UK
DATE: 5 Apr 2005
------------------- archive: http://www.genet-info.org/ -------------------
Controversy over Gene Therapy 'Breakthrough'
A 'precision' gene therapy turns out to have significant off-target
effects Dr. Mae-Wan Ho
Collateral damage from 'precision' gene therapy
A gene therapy technique, hailed as 2002's 'breakthrough of the year' in
its ability to shut down specifically and precisely any chosen gene, has
been found not to be so specific or precise after all. The technique
involves RNA interference ("Subverting the genetic text", SiS 24), the
ability of a short specific duplex sequence of RNA to target the
transcript of gene, thereby shutting it down. Unfortunately, there are
"off-target" effects on other genes and proteins.
The technique depends on a perfect match between the siRNA (small
interfering RNA) introduced and its complementary sequence in the gene
transcript. Only sequences of 19-21 base pairs are generally used, as
longer sequences induce nonspecific immune reactions.
However, various mismatches between the siRNA and its target appear to be
tolerated, so that other transcripts with similar sequences are also affected.
Peter Linsley, executive director of cancer biology for Rosetta
Inpharmatics, a company based in Seattle, Washington, USA, and a
subsidiary of drug giant Merck, was using siRNAs to design more targeted
drugs. The plan was to use siRNA to shut down a particular gene, and then
add a compound that also targets the gene to see if additional genes are
But his team found that the siRNAs were shutting down more genes than
just the one intended. "The siRNAs were dirtier than our compounds,"
Linsley said. They kept finding the same results, and finally concluded
that the siRNA could "cross-react" with other genetic targets. They had
trouble convincing reviewers to get their results eventually published in
Nature Biotechnology in June 2003.
At first skeptical of the findings, the RNA interference community was
gradually prodded by Linsley's work to look more carefully at their own
findings. "We saw more and more unexplained phenomena," admitted Rene
Benards, a cancer geneticist at the Netherlands Cancer Institute in
Amsterdam. Similarly, Phillip Zamore, a biochemist at the University of
Massachusetts Medical School in Worcester, now believes that the
limitation of the technique should have been obvious, and it was
"incredibly unreasonable" to have presumed absolute specificity.
Using microarrays to screen for off-target effects, researchers are
finding in general that a dozen genes may be affected by a single siRNA;
although Linsley has recorded on average at least 40genes affected. But
microarrays only show the effect on RNA transcripts, and not on proteins
(and microarrays themselves are proving unreliable, see "Biotech wonder
tool in disarray", this series). So the off-target effects could be even
This is especially understandable in hindsight, as geneticists have
discovered numerous species of microRNAs interfering naturally and
copiously in gene and protein functions. Putting in siRNAs is rather like
throwing a monkey wrench randomly into the incredibly complicated and
sophisticated machinery that RNA interference has turned out to be.
Predictably, proponents remain hopeful that such off-target effects may
not matter, and could be addressed by further research.
The first clinical trial of siRNA therapy was launched in October 2004 by
the Philadelphia company Acuity Pharmaceuticals on macular degeneration,
a breakdown of the small area at the back of the eye that's responsible
for acuity in vision, which causes blindness. Because the treatment is
restricted to the eye, it is hoped that the risk of off-target effects is
of less concern. Another candidate for treatment is hepatitis B, where
the hope is that the siRNA could disable the virus without causing too
much off-target damage.
But it would be irresponsible to proceed in the absence of further
research, given the sorry record of gene therapy thus far ("Gene therapy
woes", this series).
This article can be found on the I-SIS website at http://www.i-
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