Scientists at Harvard Medical School have succeeded in protecting mice against herpes infection for one week using a single application of a microbicide based on a new technology called RNA interference.
The technology, still in its infancy as a therapeutic tool, could have a powerful impact as an HIV prevention tool, according to Professor Judy Lieberman, lead investigator.
What is RNA interference?
Silencing RNAs, or RNA interference (siRNA), are short strands of RNA that target particular genes and 'silence' the activity of messenger RNA generated by those genes.
They do so, in the main, by disrupting the production of the proteins assembled according to instructions carried in RNA. The very short sequences of short interfering RNA – less than 30 base pairs – bind to identical sequences in the RNA produced by the gene whose activity needs to be blocked.
The development of siRNAs as therapeutics stems from the discovery that cells generate siRNAs of their own, to protect against aberrant messenger RNAs, to protect against viruses and to modulate gene expression pathways within a cell.
However, delivering therapeutic siRNAs from outside the cell to the right place and ensuring that they do not have any unwanted effects on the cell are still proving challenging. The potential for viral resistance to the SiRNAs is also uncharted.
In the case of HIV, the most promising approach appears to be the development of siRNAs that can target sequences of HIV RNA that will not vary from one virus to another.
SiRNAs are also being investigated in many other disease areas, for both therapeutic and preventive purposes. The results published in January in the journal Cell Host and Microbe, for example, show the potential application of siRNAs in microbicides, topical agents that can be used to prevent vaginal transmission of sexually transmitted infections.
Although much emphasis has been devoted to microbicides that can protect against HIV, protection against HSV-2 (the virus that causes genital herpes) is also a priority, especially because HSV-2 infection increases an individual’s chances of becoming infected with HIV.
The study carried out at the Immune Disease Institute at Harvard Medical School sought to silence two genes in mice, using silencing RNAs that targeted a receptor for HSV-2 (nectin-1) and an HSV-2 gene essential for replication (UL29). When these genes are silenced, the receptor should not be expressed on the cell surface, and replication should be interrupted.
The research team found that when conjugated with cholesterol, the siRNAs were able to protect against HSV-2 for up to a week after one application by silencing the nectin-1 gene. However, protection was not evident immediately; it took at least one day for protection to become apparent, as measured by a sequence of viral challenges before, at the same time as and up to seven days after administration of the microbicide containing the siRNAs.
SiRNAs may indice inflammatory or interferon responses, but there was no evidence of inflammation in the vaginal tissue of mice that received the microbicide
"People have been trying to make a topical agent that can prevent transmission, a microbicide, for many years," said Professor Judy Lieberman of Harvard Medical School. "But one of the main obstacles for this 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. This aspect has a real practicality to it. If we can reproduce these results in people, this could have a powerful impact on preventing transmission."
The researchers also see potential for siRNAs to be used to suppress herpes reactivation in women who have already contracted HSV-2.
Lieberman was recently awarded a grant from the Massachusetts Life Science Center to collaborate with a corporate partner to build on these results to develop a topical microbicide that might be suitable for human use.
In addition, she is investigating how the same approach might be used to treat HIV in a multi-institutional programme funded by the National Institutes of Health that includes researchers at the Tulane National Primate Research Center, St. George's Hospital in London, and Alnylam Pharmaceuticals in Cambridge, Massachusetts.
Wu Y et al. Durable protection from herpes simplex virus-2 transmission following intravaginal application of siRNAs trageting both a viral and host gene Cell Host and Microbe 5, 1-11, 2009.