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Getting the fat in
CAMBRIDGE, Mass.—In what could be a huge leap forward for RNA interference (RNAi) therapies, both in terms of efficacy and dosing, researchers at the Massachusetts Institute of Technology (MIT) and Alnylam Pharmaceuticals reported recently that they have successfully used RNAi to turn off multiple genes in the livers of mice.
Making their success known in the Dec. 28, 2009, issue of the Proceedings of the National Academy of Sciences, in the article "Lipid-Like Materials for Low Dose, in vivo Gene Silencing," the researchers note that they were able to silence up to five genes at a time, an advance that "could lead to new treatments for diseases of the liver and other organs."
The MIT and Alnylam researchers note that the 1998 discovery of RNAi has led to much hope, particularly in terms of the potential to silence malfunctioning genes that cause such pervasive and difficult-to-treat diseases as cancer. But delivery has been a repeatedly vexing problem, notes Daniel Anderson, senior author of the paper and a biomedical engineer at the David H. Koch Institute for Integrative Cancer Research at MIT.
"First, even as recently as a few years ago, it was challenging enough just to get siRNAs (short interfering RNAs) to work in animals at all, and one of the things we were able to show in some earlier papers was our ability to actually knock down genes in animals, especially in the liver," Anderson says. "But what it important in this latest research and that really pushes things forward is that we have developed new delivery systems that are more efficacious on a per-dose basis, so that we can knockdown with orders of magnitude better efficiency. We can theoretically get good knockdown with a hundredfold or more fewer siRNA than in the past."
As he points out, if you can use a lesser amount of siRNAs, you can therefore think of packing more types of them into a single treatment. Anderson also says that they have shown efficacy in primates, which takes them yet another step closer to human trials.
"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 RNA interference is finding a safe and effective way to deliver the short strands of RNA that can bind with and destroy messenger RNA, which carries instructions from the nucleus, note MIT and Alnylam.
Anderson and his colleagues believe the best way to do that is to wrap siRNAs in a layer of lipidoids, which can cross the fatty outer membrane of cells. 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.
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.
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.