Friday, May 4, 2007

RNAi and Bird Flu

Every year labs around the world are racing to get vaccines ready for next year’s flu season. Even if the logistical nightmare can be managed and complicated vaccines are manufactured in time, this is no guarantee that the vaccine protects against the actual flu strain that season. This is because even as we observe the new strains emerging from East Asia, once it has reached our shores, the virus is likely to have changed his outer surface making it more difficult to be recognised by the immune system. That’s what viruses have learned to do anyway. If seasonal flu is challenging enough to predict, then developing a vaccine for a pandemic flu strain that had been generated by considerable genetic drift, is a daunting task.

Here, using RNAi, and in principle other nucleic-acid based therapies for that matter, offers a number of considerable advantages. Significantly, rather than going after a moving target, RNAi allows us to aim at flu genes that are not as mutable given the structural constraints of their encoded proteins for viral replication. This means that even if a re-assorted bird flu might look quite different on the surface, many parts inside of the virus will look very similar between even divergent flu strains. These conserved parts, or better their underlying RNAs, can be computationally predicted, and it is then very straightforward to design small interfering RNAs (siRNAs) against these RNAs well before we even know that there will be a bird flu pandemic. This can be done with high statistical confidence.

Of course, this strategy is not only applicable to bird flu, but any other emerging viral threat. A number of high-quality scientific papers have been presented documenting the feasibility of this approach. Intradigm e.g. has shown in 2005 in a timely manner that siRNAs could protect monkeys from severe lung damage due to SARS. Research teams from Nastech and Alnylam have similarly documented the potential of RNAi for flu in animal models. The US government is funding much of the research and may eventually decide to stockpile siRNAs for pandemic bird flu. Concomitantly, manufacturing capabilities are also being developed.

It is further encouraging that the lung which has been exploited for eons by viruses to infect the host now emerges as a good organ for drug delivery. Specifically in the case of RNAi, it came as a rather pleasant surprise that even unformulated siRNAs could readily get into lung cells and silence their target genes. RNAi therefore not only holds promise as a rapid response to viruses, but also other diseases of the airways such as asthma and COPD. As I write, many of these conditions are the subject of pre-clinical RNAi programs and one program by Alnylam for RSV (respiratory syncytial virus) has already reached the clinic. Data from their viral challenge studies in the second half of this year are widely anticipated, and if successful, would present the first proof-of-concept for a human RNAi Therapeutic.

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