Judy Lieberman, a researcher with Harvard’s CBR Institute for Biomedical Research, has moved forward with the early-stage in vivo development of an RNAi-based microbicide that could be used vaginally or anally to prevent HIV infection, RNAi News has learned.
Lieberman, who first told RNAi News in October that she and her colleagues were in the early stages of preparing to develop such a compound (See RNAi News, 10/03/2003), has also just received a two-year grant from the National Institute of Allergy and Infectious Diseases to fund the effort.
“One of the main problems with microbicides is that in order for them to be effective you usually have to use them just before you have sex, and that’s a pretty big stumbling block,” Lieberman told RNAi News this week. “The notion is that a lot of the cells that are believed to be involved in transmitting HIV are pretty stable locally in the vagina, so if you can silence them you might be able to treat yourself every couple of weeks or every month, and be protected from HIV.”
According to Lieberman, she and her colleagues have also gathered preliminary data suggesting that duplex siRNAs can be delivered to macrophages and activated T-cells without transfection. She declined to comment more specifically on the data, given its early-stage status, but noted that the idea behind the microbicide project is to have the agent delivered locally, bypassing “a lot of the delivery issues.”
Putting the virus suppression and delivery approach together, one potentially has the recipe for an effective prophylactic HIV preparation.
The first part of the grant-sponsored project — the in vivo delivery of siRNAs to dendritic cells, macrophages, and possibly lymphocytes, in the genital mucosa of mice — is underway, Lieberman said. Macrophages and lymphocytes represent reservoirs for HIV, and dendritic cells are believed to be responsible for introducing HIV to T-cells following sexual exposure to the virus.
Lieberman said that she and her colleagues are also collaborating with Andrew Blauvelt, a researcher at the National Cancer Institute’s Center for Cancer Research, on a skin model of the female genital epithelium for the project.
“There’s no HIV model in mice — that’s the problem for us in terms of developing this,” Lieberman said. But Blauvelt has a human ex vivo skin blister model that’s “a lot like the surface of the vagina … so we’ve just begun doing experiments with him,” she said. “You can use the model to look at effectiveness … in terms of protection from HIV.”
Assuming that these early experiments prove successful, Lieberman said that the next step would be to move to primate studies. Specifically, this part of the project would evaluate the efficacy of siRNAs designed to silence simian immunodeficiency virus Gag and CCR5, as well as delivery approaches, using peripheral blood mononuclear cells from the pig-tailed macaque, Macaca nemestrina.
This step would form the basis for future delivery, toxicity, and challenge studies in the macaque model.
Lieberman said that the NIAID grant, which will cover up to $350,000 in direct costs, would not be sufficient to fund the RNAi microbicide effort beyond the mouse studies. “To do primates is very expensive, so if we can get some more preliminary data in mice, we will either apply for more money or [look to] the NIH, [which] has other mechanisms to look at things in primates,” she said. “The NIH is very supportive and interested in this project.”
As for possible support from the private sector, Lieberman declined to comment beyond stating that “I haven’t gone out looking.”
This doesn’t mean that RNAi firms haven’t found her. Lieberman does have ties to at least one RNAi company, Sirna Therapeutics. Sirna CSO Nassim Usman recently told RNAi News that his company forged a research partnership with Lieberman in June 2003, under which she is conducting research on a number of undisclosed targets for the company.
Sirna has not, however, publicly named HIV as one of its areas of interest. Officials from the company were unavailable for comment on this article.
—DM