Controversy over Gene Therapy 'Breakthrough'

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5 Apr 2005 13:31:05 -0000

 

Controversy over Gene Therapy 'Breakthrough'

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ISIS Press Release 05/04/05

 

Controversy over Gene Therapy `Breakthrough'

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A 'precision' gene therapy turns out to have significant

off-target effects Dr. Mae-Wan Ho

 

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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

http://www.i-sis.org.uk/isisnews/sis24.php), 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 affected.

 

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 more extensive.

 

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

http://www.i-sis.org.uk/GTW.php).

 

 

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