With a recently awarded NIH grant in hand and discussions with possible industry collaborators underway, MIT researcher Jianzhu Chen has set his sights on developing an RNAi-based drug to fight the influenza virus, which causes 36,000 deaths in the US alone, according to the US Centers for Disease Control and Prevention.
Chen became interested in using siRNAs against influenza more than a year ago, he told RNAi News, after his lab began collaborating with MIT professor and RNAi pioneer Phil Sharp on the use of siRNAs against CD4 and CD8.
“I think flu is a good target for siRNA, partly because infection of the influenza virus occurs locally in the lungs,” Chen said. “That would make delivery a little bit easier because you can do local delivery through intranasal administration.
“The other thing is that the influenza virus changes all the time,” he added.
“So what we did is to design siRNA against the conserved part of the [flu] genome. We compared [influenza] viruses from chickens, ducks, pigs, horses, cattle, [and] humans, and aligned those regions which have not changed, and designed siRNAs against those parts. The idea is that even when the flu virus changes, because those parts do not change, the siRNAs remain effective against all strains.”
Chen and his colleagues recently published the results of the project, which showed that the siRNAs can inhibit influenza virus production in cell lines and embryonated chicken eggs. The siRNAs, specific either for nucleocapsid or a component of the RNA transcriptase, also knocked down targeted mRNA, as well as virion RNA and its complementary RNA. (See Proceedings of the National Academy of Sciences, March 4, 2003; 100: 5, 2718-2723.)
Now, Chen said that he and his colleagues have data showing that these siRNAs can significantly reduce production of the virus in the lungs when delivered either before or after infection. Administration, he added, was achieved both intranasally and intravenously using positively charged polymers as carriers for the siRNA.
“[This] has not been published,” he said. “We are trying to write it up ... I would like to finish the paper this year, [and] I hope early next year to get it published.”
Having come up with the siRNAs and developed systems for administration, Chen said that he and his colleagues still need to elucidate how the siRNAs work in mice and cell lines. “In mice, we would [also] like to investigate how long the siRNAs remain effective [in the system], or how long after influenza virus infection you can give mice siRNA that will still have effect.”
“We’d also like to explore the combination of siRNAs to see whether they are more potent than single siRNA …[and] reduce the emergence of resistance,” he added.
Helping this process along is a $250,000-a-year grant Chen received at the end of September from the National Institute of Allergy and Infectious Diseases. The abstract of the three-year grant notes that “existing vaccines are of limited value because the influenza viruses they target are determined by ‘best guess,’ based upon recently prevalent strains,” and notes that the NIH has designated influenza a top priority area for biodefense.
Chen also expects to get some help from the private sector.
“We have a lot of interest from companies,” he said. “We are talking to … starter companies [and] other established companies.” He declined to specify which firms he is in discussions with, but said that “we should be able to work out a deal soon … by the end of the year or at least early next year.”