New 'Holy Grail' of gene-silencing technology
disabling genes that could be used to stop genetic disorders in
their tracks, such as Huntington's and some cancers.
Like the 2006 Nobel Prize winning technology, RNA-interference (RNAi), Professor Edvard Smith and Dr Rongbin Ge have developed a technique to effectively 'silence' genes.
However, instead of binding to the RNA produced by disease-causing genes - as is the case with RNAi - the molecule binds to both strands of the gene DNA simultaneously, preventing it from working.
This is the first time such a technique has ever been developed, according to the scientists, who work at the Karolinska Institute in Sweden.
Dubbed Zorro locked nucleic acid (Zorro-LNA), the molecule has the potential to be a novel drug or to serve as the basis for new drugs.
The molecules could be used to treat a myriad of human conditions related to dominant defective genes, including familial high cholesterol.
"This is a major development in the treatment not only of genetic diseases, but also of acquired diseases when microbes or toxins cause genes to go awry," said Gerald Weissmann, editor-in-chief of The Federation of American Societies for Experimental Biology (FASEB) Journal , where the research has been published online ahead of the June print edition.
"One might say these researchers have found a gene-hunter's Holy Grail for which scientists have been hunting for many years.
Zorro-LNA should give us a new, safe way of blocking the effects of errors in our genetic repertoire."
LNA is the name given to synthetic analogues of nucleic acids that have a bridging methylene carbon between the 2' and 4' positions of the ribose ring.
These RNA-mimics are then partially mixed with DNA nucleotides to form stands between 14 to 16 nucleotides long.
Each LNA strand binds to the separate stands of double-helix DNA and is held together by a third strand of 7 nucleotides - and so effectively binds to both strands of DNA simultaneously.
The overall 'Z' shape of the molecule gave it the name, Zorro-LNA.
The scientists then studied the effect of Zorro-LNA on reporter genes and found levels of gene down-regulation over 90 per cent.
Prof Smith told DrugResearcher.com: "This is a proof of concept study - it is still early days but it is a new system."
"We are now working on improving the basic construct and then applying it to different gene systems."
He explained that it is difficult to find molecules that bind strongly to double stranded DNA.
Although Zorro-LNA is similar in size and contruct to RNAi, Prof Smith said that the study shows it works in a very different way.
Since both techniques are unlikely to be 100 per cent effective, he explained, although Zorro-LNA might be used on its own, it could also be used together with RNAi to improve clinical outcomes.
Outside of genetic disorders Zorro-LNA could potentially have a number of other powerful applications similar to RNAi.
It could be used to treat other diseases where gene silencing could prove beneficial - for example in cancer, where certain genes enable the tumour to grow and spread.
It may also prove effective in changing the behaviour of cells because gene regulation can determine, for example, what cells stem cells transform into.
Another possible application would be in studying the effects of drugs on specific genes - an important part of the drug discovery process.
