Alnylam Pharmaceuticals announced this week that it has begun a program to develop an RNAi-based treatment for respiratory syncytial virus. The initiation of the program makes RSV the company’s second therapeutic development program after age-related macular degeneration.
Alnylam said it plans to develop a directly administered RNAi therapy for RSV by targeting key viral genes at the site of infection. John Maraganore, president and CEO, said in a statement that the company expects to present in vivo data from the program at “upcoming scientific meetings, and initiate clinical trials in the first half of 2006.”
RSV is a negative-sense, enveloped RNA virus that is spread from respiratory secretions, according to the US Centers for Disease Control and Prevention. It is the most common cause of bronchiolitis and pneumonia among infants and children under 1 year of age, but can lead to lower respiratory tract infections at any age, especially in elderly or patients with compromised cardiac, pulmonary, or immune systems, the CDC states.
The therapeutic program, Alnylam said, is based in part on the preclinical research of Sailen Barik at the University of South Alabama’s College of Medicine. Recently, Barik and colleagues published data in Nature Medicine demonstrating that essentially unmodified siRNAs, administered intranasally with or without transfection reagents, were able to prevent and inhibit joint infection by RSV and parainfluenza virus in mice.
The siRNAs used in the experiments targeted the viral phosphoprotein, called P, which is an essential transcriptional factor of the virus, Barik told RNAi News this week. This protein is a subunit of the functional viral RNA-dependent RNA polymerase, composed of P and another protein.
“There is no human homolog for [the] gene [encoding P], so it’s a good candidate for an antiviral,” he said. “We have shown before that if you target P, the virus is essentially stopped in its tracks — at any timepoint in infection the virus’ growth comes to a screeching halt if you use siRNA against P.”
According to the Nature Medicine paper, “when used as a prophylactic, the siRNA [treatment] not only prevented [RSV] infection, but also inhibited the disease as measured by clinical parameters. When used as a treatment drug after infection, the siRNAs are not expected to correct the pathology that has already occurred,” the researchers wrote. “Even then, inhibition of further growth of the virus resulted in more rapid cure and recovery.”
Barik noted that “the [treated] mice looked like uninfected [ones] — they looked like that hadn’t been exposed to the virus. They’re like their normal counterparts.”
Due to the cost associated with putting together an aerosolized formulation of the siRNA therapy, Barik said that he and his colleagues have only tested the intranasal formulation thus far.
“It’s hard to [administer the siRNAs in] an inhaler in the mouse … because you need a special apparatus for them to breathe in and out, and you need … a lot of aerosol, which costs a lot of money,” he explained. “So we’ve just [used] drops in the nostrils … [and] have not actually looked how far into the system the [siRNAs] might leak out from the lung.”
Barik said that this issue is currently being investigated currently but based on the low amount of drug used in the mouse experiments and the robustness of the response, he believes that the siRNAs remain, for the most part, localized in the lungs.
According to Barik, Alnylam has taken the “first right to license the [RNAi] technology,” adding that the company has assisted the researchers in the filing of a patent on the RSV drug and also agreed to conduct some additional preclinical work at it facilities.
Nagesh Mahanthappa, director of corporate development at Alnylam, told RNAi News this week in an e-mail that the company has not licensed a specific delivery technology as part of its deal with the University of South Alabama. Barik, Mahanthappa noted, used “a cationic polymer for many of his studies. Alnylam is not using any such transfection reagents in its R&D program for RSV,” but rather “a more straightforward siRNA approach,” he said.
Barik said that he continues to be encouraged by the success of his research thus far, and feels that siRNAs provide a good option for a new RSV treatment.
“You can shape [siRNAs], you can mold them as dry powders — they’re extremely stable and don’t need refrigeration, so they’re good candidate drugs that you could send to a war front, to Third World countries [in situations like the current one in Southeast Asia with] the tsunami,” he said. “All you have to do in the field is just add water. You mix [the powder] with water and basically spray it in the nose — that’s the scenario we’re thinking of at this point.”
Additionally, Barik said, “there is a high rate of cure and prevention in the mice … and I didn’t [see] any toxicity or side-effects.”