One of the chief drawbacks of RNA interference (RNAi) therapies so far has been the difficulty of delivering small interfering RNA to cells outside the liver. That's why the breakthrough from researchers at the Massachusetts Institute of Technology in delivering siRNA to endothelial cells in the lung and other organs is a big deal.
The researchers screened 2,400 nanoparticles containing siRNA in cervical cancer cells by determining if they could silence a gene for a synthetically added fluorescent protein, according to an MIT news release. Next, the winning particles were tested in endothelial cells by determining if they could interfere with a gene called TIE2. The method is described in greater detail in the May 11 issue of Nature Nanotechnology.
Crucially, and of great clinical significance, the researchers were able to reduce gene expression by more than 50% using a dose 100 times smaller than the existing standard for endothelial delivery, according to MIT. The delivery method performed best in the lungs but also worked in the heart and kidney as well as other organs--encouraging, but not terribly surprising given that endothelial cells line the inner walls of the blood vessels of many organs.
Ironically enough, the polymer-based nanoparticles did not deliver siRNA to liver hepatocytes, the target of many of the experimental therapies being developed by RNAi specialist Alnylam ($ALNY). "Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing," says the Nature Nanotechnology abstract.
According to the MIT news release, the researchers were able to block two genes associated with lung cancer and retard the growth and spread of lung tumors in mice thanks to the successful delivery of siRNA to targets in the lung.
Scientists Andrew Fire and Craig Mello won the Nobel Prize in 2006 for the discovery of the RNAi pathway by which siRNA binds to specific messenger RNA molecules and prevents them from producing a protein, thereby inhibiting gene expression.
But delivering siRNA to specific cells and organs in the body has proven to be a challenge for therapies that seek to leverage the pathway to treat diseases. Liver cells have proven to be the easiest targets so far, but the MIT researchers have shown that it is possible to target other organs, too--and with low doses of RNA, reducing side effects.
"There's been a growing amount of excitement about delivery to the liver in particular, but in order to achieve the broad potential of RNAi therapeutics, it's important that we be able to reach other parts of the body as well," said Daniel Anderson, an MIT chemical engineering professor and co-author of the Nature Nanotechnology paper, in the MIT news release.
Indeed, Alnylam COO Barry Greene previously told FierceDrugDelivery that Novartis' attempt at RNAi drug development failed because it targeted oncogenes "that are ubiquitously expressed, or expressed in tumor cells, and that's not where delivery is optimized."
Clearly, Big Pharma and others interested in commercialization should read the Nature Nanotechnology paper closely for tips.
- read the MIT news release
- here's the abstract and link to the paper in Nature Nanotechnology
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