Advance in RNA therapy technique

RNA interference (RNAi), a gene therapy with huge therapeutic potential across medicine, is back on track after a paper published in Nature this week. Research into the technique - which has garnered a Nobel prize and swathes of excitable column inches - suffered a setback last year when a group at Stanford University showed that the it was lethal to mice. The new research, performed at the Massachusetts Institute of Technology (MIT), has circumnavigated the problem by simplifying the process.

RNAi, which occurs normally in plants and animals, allows a gene to be specifically 'silenced'. Our genome operates by sending instructions from DNA in the form of mRNA (messenger RNA) for the manufacture of proteins. When RNAi occurs, tiny sections of short interfering RNA (siRNA) in complex with other proteins, bind to a gene's mRNA and destroy it before a protein can be produced.

The technique is standard practise on cultured cell lines in many research labs, with little or no ill-effects to cells - other than those intended. The problem lies in transmission of the siRNA molecules into the cells of living organisms. Currently, RNAi relies on modified viruses to export a gene called short hairpin RNA (shRNA), a precursor of siRNA, into cells. Once in the cell the gene manufactures shRNA and then uses cellular machinery to break itself down into siRNA, which can get to work nullifying its target mRNA.

The commandeering of the cell's machinery to cleave shRNA into siRNA, however, disrupts another critical intracellular system called the microRNA pathway, responsible for blocking RNA, leading to toxicity in mice.

Instead of using a virus-based delivery, MIT scientists have added the siRNA directly to cellular fluid, achieving 80 per cent silencing of target genes in the process. 'Using chemically synthesized siRNA, you can deliver sufficient siRNA to achieve therapeutically valuable gene silencing, without interfering with the cell's endogenous microRNA', said David Bumcrot, a director of research at Alnylam (an MIT startup) and one of the authors of the paper.

'We wanted to demonstrate that if you go downstream of that (export) step in the pathway, you don't get interference with the microRNA pathway', continued Bumcrot. 'With synthetic siRNAs, we deliver a defined dose and we know how long the effect lasts. If toxicity issues arise, dosing can be stopped at any time. It's much easier to control and, therefore, safer'. Details of the new technique will be published in another forthcoming coming paper.