Wednesday, June 13, 2007
RNAi by single-stranded RNAs
Sure enough, the provision of single-stranded RNAs was then shown by the Tuschl lab to be sufficient for inducing RNAi (Martinez et. al., 2002), although considerably higher concentrations were needed compared to the conventional double-stranded siRNAs in vitro. This work and potential applications thereof are the subject of a USPTO patent application by the Max Planck Society.
Nevertheless, ISIS Pharmaceuticals would claim that its antisense patents cover any therapy making use of a single-strand antisense mechanism, and in their interpretation this includes RNAi with single-stranded RNAs. ISIS’ leadership in nucleic acid technology such as nucleic acid modification and manufacturing technology is without doubt. This is also the reason why Alnylam, the leading RNAi company (of which Tuschl is a co-founder), has taken an exclusive license to a number of ISIS’ patents for the development of RNAi therapeutics, particularly for the use of modified siRNAs.
Although in tissue culture it is clear that double-stranded siRNAs are much more potent inducers of RNAi than single-stranded small RNAs, single-stranded RNAi molecules may have some utility for in vivo applications. In addition to the potential cost of goods advantage of a single-stranded versus a double-stranded approach, the delivery of single-strand RNA-like molecules to organs such as the liver may not even require as much as a formulation into a special delivery composition, as is suggested by the ability of single-stranded antisense compounds such as ISIS’ ApoB100-targeting 301012 to enter liver cells following subcutaneous injection. It is also possible, although not proven, that some of ISIS’ antisense compounds, particularly those with limited 5’ modifications, actually work through an RNAi mechanism.
The issue therefore relates to the value of a claim to a mechanism that was not even known to exist at the time when ISIS applied for patents relating to RNase-mediated gene suppression by an antisense mechanism involving ANY RNAse activity. While I think it is almost impossible that these claims will supersede the fundamental Fire-Mello and Tuschl II RNAi patents, they will probably carry some weight for the use of single-stranded RNAi molecules and ISIS is indeed pursuing such single-strand RNAi molecules for therapeutic purposes. Importantly, however, their utility in an in vivo setting still remains to be demonstrated.
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