Monday, April 28, 2008

Gene silencing gets fat

28 April 2008

A team of researchers in the US has developed fat-like nanoparticles that can carry fragments of RNA into cells, bring treatments based on gene silencing a step closer.

RNA interference, or RNAi, is a method of switching off specific genes using short stretches of RNA called siRNA. The siRNA acts as a template that effectively cancels out the section of messenger RNA code that it matches - preventing a specific disease-causing protein from being made by a cell.

Many research teams and companies are developing RNAi-based therapies, but getting the RNA into cells through the fatty membrane that surrounds them has proved challenging.

Now Daniel Anderson from the Massachusetts Institute of Technology in the US, and his colleagues, have developed a method of making and screening huge numbers of lipid-like materials able to carry siRNA into cells where they can go to work silencing genes.

The team developed chemical methods to make a large library of lipid-like
materials called lipidoids. These form nanoparticles with nucleic acids such as RNA and DNA and carry them across cell membranes. Their methods were based on addition reactions between alkyl acrylates or alkyl acrylamides and primary or secondary amines.

'With the right starting materials, we can simply mix the reagents together and let the mixture cook - there's no need for a solvent or for multiple purification or protection steps. And we get a pretty complete conversion,' says Anderson.

The researchers synthesised a library of over 1200 lipidoids, and screened them for their ability to deliver siRNA into cells grown in a dish. The effective delivery agents were then tested in mice by attaching the agents to siRNAs that interfered with a blood clotting agent called factor VII, which is expressed in the liver. Using blood and liver tissue samples, the researchers were able to test for the levels of the mRNA they were looking to eliminate to determine how effective the treatment had been. They then went on to test the materials in other animal species including mice, rats, and monkeys.

"It's definitely a big step forward"
- Simone Hess

Simone Hess, who is developing RNAi therapeutics at the Max Planck Institute for Infection Biology in Berlin, Germany, describes delivery as 'the big issue' for the field. '[This study is] definitely a big step forward,' she says.

But Hess points out that the lipidoids aren't able to target the delivery to specific cells. A number of other research groups are experimenting with siRNAs attached to antibodies that target, for example, cancer cells.

Anderson agrees that targeted delivery is important for RNAi therapies, and is currently working on the synthesis of materials able to target specific cell types. 'A key thing about this study is that it greatly expands the collection of materials we can think about using.'

Victoria Gill


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