Sunday, March 22, 2015

Follow-Up to Simplified GalNAc-RNAi Trigger Discussion

Just days after the Matsuda et al. publication on simplified, non-triantennary GalNAc-RNAi triggers (the subject of the previous blog entry), another related paper from Alnylam came out (Rajeev et al. 2015). 

The Rajeev et al. publication further supports that monomeric GalNAc designs as pioneered by Arrowhead Research for the use in RNAi Therapeutics and others (e.g. Matulic-Adamic et al., 2002) before for non-RNAi Oligo Therapeutics applications allow for effective ASGPR receptor recognition and subsequent gene silencing.  

The main difference to the Matsuda paper was that instead of GalNAc-modified nucleotide monomers, non-nucleosidic GalNAc monomers were employed (note: the Matulic-Adamic et al. also explored both nucleoside- and non-nucleoside-based monomeric clustering GalNAc strategies). They, however, were also appended to the 3’ end of the passenger strand as part of the phosphoramidite-based RNA synthesis.

The use of non-nucleosidic phosphoramidite monomers further simplifies the chemistry demands and thus cost of goods of GalNAc-siRNAs.

Ironically, not only does this paper also fail to cite the seminal Arrowhead and Matulic-Adamic research, this significant effort to get away from the apparently costly triantennary design is also at odds with Alnylam’s claims in July 2014 that a patent covering bi- and triantennary conjugates designs ‘broadly cover[ed] conjugate-based delivery of RNA Therapeutics’.

Obviously, if non-bi- and triantennary designs work, then one cannot consider the issued patent to broadly cover conjugate-RNAi triggers.

It will now be interesting to see how broad the claims will be that the patent offices will grant related to the simplified designs.  The re-writing of history effort obviously is not aimed at impressing investors or enabling the field, but part of a GalNAc IP landgrab effort, ideally resulting in the issuance of claims covering any monomeric GalNAc designs.

The one thing that I would like to give Alnylam credit for is that they will put significant resources behind the technologies they consider promising- whether they invented, own, or have a license to them or not- and thus advance RNAi Therapeutics as a field.


Anonymous said...

are we expecting a cure soon for HBV? If so is it really as far as 10 years from now?

Anonymous said...

No comment about the amazing outcome in the BIIB Alzheimers trial or the still to be reported 6mg data.

Must be under contract to discuss all and sundry save for this one.

By Dirk Haussecker. All rights reserved.

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