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RNAi-Based Topical Treatment Protects Against Herpes

NEW YORK (GenomeWeb News) – A new study suggests an intra-vaginal, topical treatment containing a combination of two different small interfering RNAs can offer lasting protection against herpes simplex virus-2 infection in mice.

In a paper appearing online today in Cell Host & Microbe, a team of researchers from Harvard University, Albert Einstein College of Medicine, Alnylam Pharmaceuticals, and Dana Farber Cancer Institute demonstrated that they could block HSV-2 replication and uptake by mouse cells using an siRNA cocktail targeting a viral gene called UL29 and a host gene called nectin-1. By linking the siRNAs to modified cholesterol molecules, they created a topical treatment that thwarted up to 80 percent of HSV-2 infections.

"I think the most significant part of the paper is that we were able to see protection that was immediate but also long-lasting," co-senior author Deborah Palliser, a microbiology and immunology researcher at Albert Einstein College of Medicine, told GenomeWeb Daily News, adding that this treatment did not cause any obvious side effects.

The team found that the topical treatment was effective if applied between a week before — and a few hours after — herpes exposure. The researchers expressed enthusiasm about these results, noting that humans are more apt to actually use such treatments if they don’t have to be applied immediately before potential HSV-2 exposure.

"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," co-senior author Judy Lieberman, a pediatric and immune disease researcher at Harvard Medical School, said in a statement. "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."

Roughly 536 million people around the world are infected with HSV-2. Although the virus isn’t deadly in adults, it can increase an individual’s susceptibility to HIV-1 and can cause brain damage or life-threatening complications in infants.

Previous research indicated that intra-vaginal application of siRNAs targeting UL27 and UL29 inhibited HSV-2 transmission in mice. But this protection did not last long. And attempts to increase the protection by upping the amount of siRNA used were unsuccessful, since boosting the amount of transfection lipid actually increased the risk of HSV-2 infection, Palliser explained.

Consequently, the team decided to forego the transfection agent for the latest research, instead using a modified cholesterol delivery system. That involves fusing siRNAs to cholesterol molecules — an approach developed by collaborators at Alnylam, Palliser said.

These siRNAs were directed against two genes: UL29, a herpes gene involved in viral replication, and nectin-1, a host gene that codes for a vaginal cell surface protein that binds the herpes virus.

Experiments in mouse cell cultures and mouse models indicated that the siRNAs curbed UL29 and nectin-1 gene expression in vaginal cells. And in mouse models, the researchers found that the intravaginal topical siRNA treatment protected up to 80 percent of mice challenged with HSV-2.

In a statement issued today, Muthiah Manoharan, vice president of drug discovery at Alnylam, said the results "point to the potential for a cholesterol conjugate approach for topical RNAi therapeutic applications, including mucosa and skin."

The treatment had no obvious side effects and did not activate genes involved in inflammation or interferon response genes. In particular, the researchers were concerned that knocking down a host gene such as nectin-1 could have adverse effects. But based on the results in mice, that doesn’t seem to be a problem — at least so far.

Even so, the authors cautioned, there is a chance that siRNAs targeting nectin-1 could pose a risk during pregnancy since the gene may have a role in development. And because nectin-1 seems to be involved in forming cellular junctions, Palliser noted, extended or repeated use of siRNAs knocking down nectin-1 could potentially cause epithelial problems. On the other hand, she said, such epithelial effects may not be a problem given the turnover of vaginal tissue during the menstrual cycle.

Before the team attempts to extend their siRNA-based treatment to humans, Palliser said, they will first need to test it in both explant models and non-human primates. If those are successful, she predicts that it will take between three to five years for the treatment to enter clinical trials. In the meantime, she noted, researchers need to tweak the topical formulation so that siRNAs are delivered in a gel or other substance rather than the buffered saline solution currently used.

The results may have implications for HIV too, both because decreasing the frequency of any sexually transmitted disease also decreases HIV prevalence, and because it may be possible to develop similar siRNA-based HIV treatments by targeting HIV-specific genes and receptors.

"We would also like to apply the results of this study to developing a topical microbicide to prevent HIV-1 infection, an urgent global health need given the failures of HIV vaccine development," the authors wrote.

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