Stabilising RNAs enhances gene silencing in tumours
25 January 2010
South Korean scientists have found a way to stabilise therapeutic RNA molecules, using chemical modifications, so that they can be more smoothly trafficked into cells. The stabilised structures have already proved to be more effective for targeting tumours in mice.
Short stretches of RNA referred to as small interfering RNAs (siRNAs) can be used to dampen gene expression in diseased cells - the recognition of their therapeutic potential, against cancer particularly, has spawned a swathe of biotech start-ups in the last few years. But progress has been hampered by difficulties in delivering the molecules to target cells, as in complex with carrier polymers they can be very unstable.
The newly modified siRNAs, conceived by researchers at the Korea Advanced Institute of Science and Technology in Daejeon, are more compact, more stable and more easily taken up by cells. As lead researcher Tae Gwan Park explains, they are formed by combining several siRNAs in one multimeric structure. This structure is held together by hydrogen bonds and disulfide links, which can be broken once inside the cell to yield intact monomers capable of targeting specific gene sequences. The higher charge density of the multimeric siRNAs allows them to form more stable complexes with cationic polymers.
'The concept itself is clever and a reasonable one to pursue further,' says David Corey, who works on RNA interference at the University of Texas Southwestern Medical Center in Dallas, Texas, US. But he isn't particularly excited by the results the team have shown so far - the data 'aren't especially strong', he says.
Image analyses reveal that, in complex with cationic polymers, the modified structures can be smaller by several hundred nanometres than 'naked' siRNA molecules. And when injected into mice with tumour grafts, the complexes appeared to be more effective at silencing genes for a fluorescent protein expressed in the tissue.
The next step is to prove the molecules work as therapeutics. 'We are now testing whether anti-cancer multi-siRNA complexes, when administered systemically, could be specifically targeted to solid tumour tissues and whether the growth of tumour tissues could be retarded,' says Park. 'The current formulations are also being tested for topical wound healing.'
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H Mok, et al, Nature Materials, 2010, DOI: 10.1038/NMAT2626
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