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By
Shaoni Bhattacharya
Human liver cells harbouring the hepatitis C virus
can be selectively targeted and destroyed by a new gene
therapy approach, according to new research.
The key is a genetically-engineered "suicide" gene,
delivered aboard a harmless virus, which is triggered
only when it enters a hepatitis-infected cell.
The two current treatments for the debilitating liver
disease - alpha interferon and ribavarin - can reduce
the level of infection, say researchers, but the virus
usually comes back.
The new gene therapy approach could one day "offer
the potential of a total cure" for many people, says
virologist Christopher Richardson, at the Ontario Cancer
Institute in Toronto, Canada, and one of the research
team. It might also help tackle other viruses, such as
HIV.
About 200 million people worldwide are affected by
hepatitis C and infections are increasing. In advanced
cases, the virus causes the liver to fail completely or
become cancerous.
Achilles heel
The research began when Richardson and colleague Eric
Hsu identified an "Achilles heel" in hepatitis C - a
unique protease enzyme produced by the virus.
Some proteases in human cells trigger proteins to
kick-start the process by which the cell commits
suicide. So the team removed the genetic code that
allows the protein to recognise the human protease and
replaced it with code specific to the hepatitis C
protease.
The DNA for the modified protein was then smuggled
into cells using a harmless adenovirus. If a cell is
infected, then the viral protease causes it to order its
own death. "It's like a suicide vector, a smart bomb,"
Richardson told New Scientist.
No rebound
The therapy successfully cleared low and medium level
hepatitis C infections in mice with implanted infected
human liver cells. In mice suffering high levels of
infection, the gene therapy slashed levels of the virus
by a factor of 1000
Importantly, the virus did not "rebound" after the
gene therapy, as it can do with existing treatments.
This is true for at least 28 days after gene therapy and
the team is now doing further work to see if this effect
lasts longer.
"It's an incredibly novel approach," said Nigel
Hughes, chief executive of the British Liver Trust and
an adviser on the UK government's strategy to tackle
hepatitis C. "But I have some reservations. If you had
this massive cascade of cells dying in the human liver,
what would the body's response be? Would you create more
harm?"
The approach is "futuristic", admits Richardson: "It
is very drastic and we would say it should not be used
immediately for human trials." An intermediate approach
could be to apply the therapy outside the body, he says.
In an ex vivo therapy, relatively healthy
liver cells could be extracted from patients with an
advanced infection, cultured and then exposed to the
gene therapy. This would kill any infected cells,
meaning healthy cells could be transplanted back and
restore some of the liver's function.
Journal reference: Nature Biotechnology
(DOI:10.1038/nbt817)
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