Monday, September 15, 2014
Wednesday, September 10, 2014
Wednesday, September 3, 2014
Tuesday, August 26, 2014
While RG7800 has the obvious advantage of being orally bioavailable versus the need for intrathecal administration of ISIS-SMNRx, in terms of molecular outcome, exon inclusion in spinal motor neurons, it appears to be lacking: a ~70% increase compared to ~100-150% increases in the good SMN2 isoform achieved by ISIS-SMNRx in two clinical trials in SMA infants and children, and even more than that in rodent studies before (Passini et al. 2011). However, RG7800 achieves SMN2 splice modulation not just in the motorneurons of the CNS, but in many other places, in and outside the CNS.
As a result, and also given the controversy around the discovery of ataluren (artefact or not) and the fact that PTC Therapeutics itself can only remotely speculate on the mechanism of action of RG7800, I acknowledge the publication as interesting, but am not ready to jump on board just yet.
Friday, August 22, 2014
Wednesday, August 20, 2014
81. An isolated double-stranded RNA molecule, comprising:
(i) a sense strand and an antisense strand that form a double-stranded region of up to 25
base pairs, said sense strand having an identity in the double-stranded region of at least 85
percent to a target RNA molecule; and
(ii) at least one strand having a single-stranded 3’-overhang, wherein said 3’-overhang
has been stabilized against degradation; and
(iii) at least one nucleotide analogue,
wherein said RNA molecule is capable of target-specific RNA interference.
Note that Dicerna's RNAi triggers make use of the 2'-O-methyl modification which sometimes is found in the 3' overhang and can also have stabilizing activity. Taken together, this claim indeed questions Dicerna's RNAi triggers, and although I would expect vigorous debate around whether 25 base-pairs are covered by the patent's description requirements should it come to a patent litigation, the assumption is that Alnylam's new patent rightfully questions many, if not most of the RNAi triggers used by Dicerna currently.
Since I'm at it, the new patent also comes awfully close to the asymmetric RNAi trigger designs by RXi Pharmaceuticals and others (asiRNAs). RXi e.g. uses dsRNA lengths of below 15bp with the guide strand having a long 3' overhang. I am a bit surprised that Alnylam got just enough extension both below and above their traditional 19-23bp stronghold to start overlapping with some asiRNA and Dicer-substrate designs.
Regardless, I stand by my point that Alnylam has re-invigorated their patent-related press releases in order to explain the valuation gap to its peers in the public markets. The original blog entry follows here:
This morning, Alnylam greeted the competition with another IP-related press release. It wrongly claims that a patent it just obtained covers competing technologies. This suggests that it either lacks an understanding of RNA technology basics or that it is afraid that the market will come to understand that the valuation difference to its peers has no basis in either a commercially more attractive clinical pipeline, a superior patent estate, or simply better technology.
[Note: in the original entry I mistakenly said Dicerna's triggers were 27 base-pairs; to be precise, they are 25/27 designs with 25 base-pairs and a 2 nucleotide 3' overhang on the guide.]
While I still consider that endo-lysosomal stability of the naked RNAi trigger is critical for approaches like GalNAc-siRNA conjugates, the new DPC-enabled ARC520 results strongly indicate that another critical factor lies downstream of endo-lysosomes. This is because in the DPC approach which involves strong endosomolytic activities that should activate soon after endocytic uptake, the risk of the RNAi trigger being degraded in the endo-lysosomes should be low. Similarly, there should be little contribution to gene silencing from RNAi triggers that get released into the cytoplasm in a delayed fashion.
RISC-optimized ultra-stable single-strand RNAi triggers
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