| Departments — Benchmarks | Spring 2009 |
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Rites of Passage Now, Judy Lieberman ’81, an HMS professor of pediatrics at Children’s Hospital Boston and a senior investigator at the Immune Disease Institute, has overseen the development of a topical treatment that, in mice, disables genes necessary to herpesvirus transmission. The treatment uses the intracellular mechanism called RNA interference (RNAi) to deal the virus a molecular one-two punch that knocks out both the bug’s ability to replicate and the host cell’s capacity to take up the virus. The treatment is just as effective when applied from one week before to a few hours after exposure to the virus. So the basic biology of the prophylactic is responsive to real-world demands. The findings appear in the January 22, 2009, issue of Cell Host and Microbe. Now and Then “People have been trying to make a topical agent that can prevent transmission for many years,” says Lieberman. “But one of the main obstacles to this goal is compliance. One of the attractive features of the compound we developed is that it creates in the tissue a state that’s resistant to infection, even if applied up to a week before sexual exposure. If we can reproduce these results in people, use of this microbicide could have a powerful impact on preventing transmission.” According to the World Health Organization, approximately 536 million people worldwide are infected with herpes simplex virus type 2 (HSV-2), the most common strain of the herpesvirus. Women are disproportionately affected, with potentially serious consequences. The virus can pass easily from mother to newborn during delivery, and untreated infants risk brain damage and even death. While HSV-2 alone is not life threatening for adults, infection does increase a person’s vulnerability to other viruses such as HIV. In order for the herpesvirus to infect a host cell, two conditions must be met. First, the virus must enter and take over the cell. Second, the virus must reproduce itself. Lieberman’s topical treatment uses RNAi to foil both events. Method Acting RNAi, a biological process identified barely a decade ago, has transformed the field of biological research. This process, which occurs naturally in the cells of all multicellular organisms, regulates the translation of genetic information into proteins. By introducing tiny RNA molecules into cells, researchers can target a gene and block its ability to build protein molecules, essentially disabling the gene. While RNAi has profoundly improved scientists’ ability to probe and interrogate cells in Petri dishes, therapeutic breakthroughs using the process have proved elusive. Researchers have had difficulty targeting the delivery of the tiny RNA molecules into selected cells and tissues in a living organism. For this study, Lieberman and her team modified a delivery technique they had previously developed so as to treat murine cells with strands of RNA that could block certain genes from producing proteins key to the herpesvirus infection process. The technique allowed the researchers to fuse the RNA strands to cholesterol molecules, which helped chaperone the RNA molecules through the cell membranes. When applied as a topical solution, the RNA molecules could be fully absorbed into the vaginal tissue, protecting the mice against a lethal dose of administered virus. One RNA molecule in the topical solution targeted the herpes gene UL29, a gene the virus uses in its replication process. Another RNA molecule targeted the actions of Nectin-1, a surface protein on cells in the vaginal tissue. Nectin-1 binds to extracellular substances, including herpesvirus, and ushers them into the cell. By shutting down Nectin-1, the virus cannot get into the cells. The actions of either RNA molecule would be sufficient to block the virus. But delivered together in this RNAi cocktail, they prompt the host cell to block the virus’s entrance and to implement a backup scheme that wipes out the invader’s ability to multiply if it does enter the cell. “As far as we could tell,” says Lieberman, “the treatment caused no adverse effects, such as inflammation or any kind of autoimmune response. And while knocking out a host gene can certainly be risky, we didn’t see any indication that temporarily disabling Nectin-1 interfered with normal cellular function.” Lieberman recently received a grant for work with a corporate partner on a topical microbicide suitable for human use. In addition, she is investigating how the study’s approach might be used to treat HIV.
David Cameron is associate director for media relations at Harvard Medical School. Photo: ©iStockPhoto.com/Duncan Walker |
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