MIT research group uses RNA interference to shut off inflammation
CAMBRIDGE, Mass.—Harnessing the power of RNA interference, a consortium of East Coast scientists may have discovered a targeted way to curb inflammation, opening the door for the development of new treatments for diseases like heart disease, cancer and atherosclerosis.
Noting that RNA interference and its potential to shut off any gene in the body has been a focus of scientists since 1998, the team set out to find a safe and effective way to deliver short strands of RNA that can bind with and destroy messenger RNA, which carry instructions from the nucleus. The study resulting from these efforts appears in the Oct. 9 issue of Nature Biotechnology.
The study describes the merging of in-vivo RNA interference with recent insight into monocyte biology, opening a new translational avenue to approach the many diseases driven by recruitment of these cells," says Daniel Anderson, associate professor in the Harvard-MIT Division of Health Sciences and Technology.
Anderson was joined by MIT Prof. Robert Langer, as well as scientists from Massachusetts General Hospital, Harvard Medical School, Brigham and Women's Hospital, Alnylam Pharmaceuticals, the Harrison School of Pharmacy and Seoul National University in South Korea.
In the study, the researchers described how they delivered short strands of RNA packaged in a layer of lipidoids, or fat-like molecules. Inflammatory monocytes depend on the chemokine receptor CCR2 for distribution to injured tissue and stimulate disease progression, the researchers note in the study. Monocytes are recruited by a molecule called MCP1 that's released at injury sites. MCP1 binds to a protein on the surface of monocytes called the CCR2 receptor, stimulating the cells to travel to the injury site and launch inflammation.
Precise therapeutic targeting of this inflammatory monocyte subset could spare innate immunity's essential functions for maintenance of homeostasis—thus limiting unwanted effects, according to the MIT team.
"Most clinically approved drugs may have molecular specificity, but broadly target cells in tissues they distribute to, including cells that should be spared to avoid unwanted side effects. For example, steroids have been tested in patients with myocardial infarction with disastrous outcomes, and their side effects (fluid retention, diabetes) make them an unlikely candidate for treating cardiovascular disease," they point out. "Other potent immunosuppressive drugs such as methotrexate, used for treatment of rheumatoid arthritis, also lack cellular specificity. Therefore, while these drugs suppress inflammation, they also diminish protective functions of the immune system which are involved in the resolution of inflammation, wound healing and defense against infection.
In general, delivery of drugs by nanoparticles can increase their concentration at the site of action, which may partially explain the advantage in efficiency when we compared siCCR2 treatment with small-molecule CCR2 inhibitors."
For this study, the researchers designed an RNA sequence that blocks the gene for the CCR2 receptor. Without that receptor, the monocytes do not respond to MCP1, so in theory, the treatment should block much of the inflammatory response.
What they discovered when testing the RNA nanoparticles in mice with atherosclerosis and cancer is that inflammation was greatly reduced—in fact, even tumors grew more slowly in the treated mice. In addition, they also found reduced inflammation when they treated mice that had recently had a heart attack.
Specifically, the treatment attenuated their number in atherosclerotic plaques, reduced infarct size following coronary artery occlusion, prolonged normoglycemia in diabetic mice after pancreatic islet transplantation and resulted in reduced tumor volumes and lower numbers of tumor-associated macrophages. Taken together, the siRNA nanoparticlemediated CCR2 gene silencing in leukocytes selectively modulates functions of innate immune cell subtypes and may allow for the development of specific anti-inflammatory therapy, the researchers wrote in their paper.
The researchers note that their approach is distinct from previous work on gene silencing in leukocytes.
"To our knowledge, this is the first demonstration of siRNA delivery to the inflammatory Ly-6C high monocyte subset," they wrote in the paper.
Anderson says that with these findings, the team has "a lot of steps now." The team is now developing manufacturing techniques that could consistently yield large numbers of identical particles, which would be necessary for potential clinical trials.
"One of the things we are interested in is translating this stuff to people. We're interested in delivering RNA to tumors and to the liver, and reengineering the chemistry of these particles to make them more effective and safer to hit the cells," he says.
Anderson notes that the researchers have a long working relationship with Alnylam Pharmaceuticals as a commercial partner.