New RNA interference technique can silence up to five genes

December 28, 2009 by Anne Trafton

Researchers at MIT and Alnylam Pharmaceuticals report this week that they have successfully used RNA interference to turn off multiple genes in the livers of mice, an advance that could lead to new treatments for diseases of the liver and other organs.

Since the 1998 discovery of RNA interference — the naturally occurring phenomenon in which the flow of from a cell's to the protein-building machinery of the cell is disrupted — scientists have been pursuing the tantalizing ability to shut off any gene in the body. Specifically, they have been trying to silence malfunctioning genes that cause diseases such as cancer.

The new delivery method, described in the Proceedings of the National Academy of Sciences, is orders of magnitude more effective than previous methods, says Daniel Anderson, senior author of the paper and a biomedical engineer at the David H. Koch Institute for Integrative at MIT.

"This greatly improved efficacy allows us to dramatically decrease the dose levels, and also opens the door to formulations that can simultaneously inhibit multiple genes or pathways," says Anderson.

The key to success with is finding a safe and effective way to deliver the short strands of RNA that can bind with and destroy , which carries instructions from the nucleus.

Anderson and his colleagues believe the best way to do that is to wrap short interfering RNA (siRNA) in a layer of fat-like molecules called lipidoids, which can cross cells' fatty . Using one such lipidoid, the researchers were able to successfully deliver five snippets of RNA at once, and Anderson believes the lipidoids have the potential to deliver as many as 20.

The team at MIT, along with Alnylam researchers, have developed methods to rapidly produce, assemble and screen a variety of different lipidoids, allowing them to pick out the most effective ones.

In a previous study, the researchers created more than 1,000 lipidoids. For their latest study, they picked out one of the most effective and used a novel chemical reaction to create a new library of 126 similar molecules. The team focused on one that appeared the most promising, dubbed C12-200.

Using C12-200, the researchers achieved effective gene silencing with a dose of less than 0.01 milligrams of siRNA per kilogram of solution, and 0.01 milligrams per kilogram in non-human primates. If the same dosing were translated to humans, a potential therapy would only require an injection of less than 1 milliliter to specifically inhibit a gene, compared with previous formulations that would have required hundreds of milliliters, says Anderson.

Other authors from MIT include Kevin T. Love, Kerry P. Mahon, Christopher G. Levins, Kathryn A. Whitehead and Institute Professor Robert Langer.

The MIT/Alnylam team hopes to start clinical trials within the next couple of years, after figuring out optimal doses and scaling up the manufacturing capability so they can produce large amounts of the siRNA-lipidoid complex.

Explore further: Researchers developing molecular delivery vehicles for genetic therapies

More information: "Lipid-Like Materials for Low Dose, in vivo Gene Silencing," Kevin T. Love, Kerry P. Mahon et al. Proceedings of the National Academy of Sciences, week of Dec. 28, 2009.

Related Stories

Novel laboratory technique nudges genes into activity

January 29, 2007

A new technique that employs RNA, a tiny chemical cousin of DNA, to turn on genes could lead to therapeutics for conditions in which nudging a gene awake would help alleviate disease, researchers at UT Southwestern Medical ...

Polymers hold promise for safer gene delivery

September 7, 2007

In work that could lead to safe and effective techniques for gene therapy, MIT researchers have found a way to fine-tune the ability of biodegradable polymers to deliver genes.

Weakened RNA interference reduces survival in ovarian cancer

December 17, 2008

Levels of two proteins in a woman's ovarian cancer are strongly associated with her likelihood of survival, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports in the Dec. 18 ...

Explained: RNA interference

November 12, 2009

Every high school biology student learns the basics of how genes are expressed: DNA, the cell’s master information keeper, is copied into messenger RNA, which carries protein-building instructions to the ribosome, the part ...

Recommended for you

How the finch changes its tune

August 3, 2015

Like top musicians, songbirds train from a young age to weed out errors and trim variability from their songs, ultimately becoming consistent and reliable performers. But as with human musicians, even the best are not machines. ...

Machine Translates Thoughts into Speech in Real Time

December 21, 2009

(PhysOrg.com) -- By implanting an electrode into the brain of a person with locked-in syndrome, scientists have demonstrated how to wirelessly transmit neural signals to a speech synthesizer. The "thought-to-speech" process ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.