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Targeting RNA
Small RNA molecules home in on cancer cells

Results: In a step toward enlisting small interfering RNA molecules (siRNAs) as drugs that turn off specific disease-causing genes, researchers from Harvard Medical School have for the first time induced siRNAs to enter only targeted cells in lab animals. They tagged the siRNAs with an antibody fragment that binds specifically to a cell-surface receptor. In one lab-dish experiment, they found that their tagged siRNAs were absorbed only by mouse melanoma cells engineered to carry this receptor and not by normal melanoma cells. Next, they injected the siRNAs–designed to shut down known cancer-causing genes–into mice that had had the engineered melanoma cells implanted in them. They found that after nine days the tumors were about half the weight of those in control-group mice.

Why It Matters: By turning off certain genes in a process called RNA interference, small interfering RNA molecules could become a new class of drugs for a wide range of diseases, such as cancer, cystic fibrosis, and certain infectious illnesses. So far, the biggest research challenges have been delivering these fragile molecules throughout the body in a stable form and ensuring that they home in on specific cells. While other researchers had stabilized siRNAs so that they remained intact in the bloodstream of lab animals, the Harvard researchers, led by Judy Lieberman, have taken the next big step: shuttling the molecules to specific cells.

Methods: In one set of experiments, the researchers engineered mouse melanoma cells to produce a receptor normally found on the surface of the HIV virus. They used this receptor because an antibody tag specific to it had already been shown to deliver DNA to HIV-infected cells, and they wanted to see if the same tag would also work with siRNAs. They fused a fragment of an antibody specific to that receptor to another protein, which they then bound to three different siRNA molecules, each of which shut down a different cancer gene. They introduced the antibody-tagged siRNA molecules, alone and in combination, into lab dishes containing the engineered melanoma cells and measured the effect on cell division. Then they implanted the cancer cells in the flanks of mice, under the skin; injected the mice with the siRNAs; and measured the effects on tumor volume and weight.

Next Step: The researchers need to show that they can target siRNAs to receptors naturally present on tumor cells. And they need to check that their siRNA molecules don’t elicit undesirable inflammatory responses in lab animals and are not rapidly degraded by blood enzymes. – By Corie Lok

Source: Song, E., et al. 2005. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nature Biotechnology 23:709-717.

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