Posted on 04/21/2003 5:13:55 PM PDT by Prince Charles
Genetic "smart bomb" knocks out hepatitis
19:00 20 April 03
NewScientist.com news service
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)
Shaoni Bhattacharya
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