Respiratory syncytial virus is best known as the most common cause of hospitalization among infants and children under 1 year of age, and the most common viral cause of death in children under age 5, though it also affects elderly and immunocompromised patients.

In the U.S. alone, RSV causes 125,000 hospitalizations and close to 2,000 deaths annually. Globally, the World Health Organization estimates that there are 64 million infections, leading to 160,000 deaths annually.

"[In the U.S.], the estimated cost by the CDC is 300 million per year, and that's not including parental time lost not working or not being productive due to lost sleep. The cost of treating a hospitalized RSV kid can run $70,000. It's a huge market," said Sailen Barik, professor of biochemistry and molecular biology at the University of South Alabama.

Barik is senior author of "Inhibition of respiratory viruses by nasally administered siRNA," which appears in the January 2005 issue of Nature Medicine. The paper describes preclinical studies demonstrating the ability of short interfering RNAs to prevent and treat infection with both respiratory syncytial virus (RSV) and parainfluenza virus (PIV), two viruses that cause lower respiratory tract infections in children.

"[SiRNAs] provide a better approach compared to traditional antivirals, because they provide both prophylactic and therapeutic avenues for RSV infection. The small-molecular approach comes in at the tail end of infection; they cannot be used in a prophylactic way, because of their adverse effect profile," Shyam Mohapatra, professor of allergy and immunology and director of basic research at the Joy McCann Culverhouse Airway Disease Center, University of South Florida, told BioWorld Today in an email interview. He is senior author of "Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene," which appears back-to-back with Barik's paper and was published by researchers from the University of South Florida, TransGenex Nanobiotech Inc., the James A. Haley Veteran's Hospital and the H. Lee Morritt Cancer Center, all located in Tampa, Fla.

Huge Market, Dearth Of Drugs

Despite the number of RSV infections, there are very few drugs available to treat RSV, and some of those are nonspecific. In fact, for mild cases of RSV, the most likely treatment is palliative - in other words, baby Tylenol and plenty of fluids.

For serious cases, three treatment options exist: MedImmune Inc.'s Synagis (palivizumab), a humanized monoclonal antibody; the broad-spectrum antiviral ribavirin; and interferon treatment. All three are expensive and can have serious side effects, but still represent the best available therapies.

Though both papers describe the use of siRNAs to combat RSV infection, that's pretty much where the similarities end. "The technology is the same, but the underlying philosophy is very different," Barik said. The siRNA used by Barik and his colleagues targets a phosphorylation transcription factor of viral RNA polymerase that is essential for viral replication. They tested the siRNA against both RSV and PIV, a related virus with a very similar phosphoprotein. PIV takes up where RSV leaves off, preferentially affecting children 2 to 4 years old.

"Sometimes PIV gets neglected" because people tend to focus on RSV, Barik said. "But it's second only to RSV in the [viral] deaths it causes in little children."

The scientists found that when given intranasally, the siRNA inhibited the replication of both RSV and PIV in mice, and could prevent some of the clinical symptoms of infection when given either before or shortly after infection. Those effects were not accompanied by a rise in interferons.

In a surprising finding, siRNA given without a carrier also was somewhat effective in quashing infection. "Normally, cells are very reluctant to take up foreign nucleic acids," Barik explained. To enhance uptake, the RNA thus is complexed with transfection virions, but those themselves can have toxic side effects. "From a theoretical standpoint, the less you introduce into the body, the better," Barik said. The ability of the siRNAs described here to work without transfection virions suggests that they might make "a very clean drug."

Barik said he doesn't know why the transfection virion was not necessary, but speculated that "the lung may be a bit more permeable than other tissues, because of its function. And the infected lung may be even more permeable because it may be a little bit damaged."

In contrast, the siRNA described by Mohapatra and his colleagues takes aim at the virus-host interaction via the NS1 gene, or nonstructural gene. NS1 is "the first gene to be transcribed and is considered both an early and late response gene. NS1 gene down-regulates host IFN response, which is the host's own way of combating virus infection," Mohapatra said.

Mohapatra and his colleagues showed that mice treated with siNS1 nanoparticles showed decreased virus titers and decreased lung inflammation. Administration either before or after infection with RSV was effective. Mechanistically, the effects were due to up-regulation of the interferon response.

They did not attempt to deliver the siRNA without a carrier. But instead of using a virion, they complexed the siRNA to chitosan - nanoparticles that have high affinity for the lungs and are ultimately metabolized. Mohapatra said that "the vector-driven expression of siRNA is important as it provides long-term expression with smaller amounts of DNA." That could lead to treatments being given only every one to two weeks.

It is not surprising, given the large potential market that exists for RSV treatments, that both papers have industrial connections. Alnylam Pharmaceuticals Inc. has licensed the siRNAs described by Barik, and announced in early January that it was initiating a therapeutic development program with them. Alnylam scientists presented further preclinical studies on their efficacy at a recent Keystone symposium in Breckenridge, Colo. The company expects to enter the clinic in 2006.

"Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene" is co-authored by scientists from TransGenex, which manufactured the nanoparticles used in the studies for complexing the siRNA. TransGenex has licensed the nano-siRNA approach for RSV infection from the University of South Florida.