Friday, August 26, 2011

Brewed up in Seattle: Tekmira and Halo-Bio Seek to Capitalize on Multi-Targeting Potential of RNAi Therapeutics with Multi-Valent RNAi Triggers

It must have been over either coffee, the fuel of scientific discovery and frequent source of business development inspiration, or beer, a beverage that you may enjoy but not mix with business, that Seattlelites Mark Murray (CEO of Tekmira) and Todd Hauser (CEO/inventor of Halo-Bio) initially came up with the idea of joining forces to revolutionize one of the attractions of RNAi Therapeutics: Multi-Targeting, especially for the treatment of complex diseases, cancer and viral infections (see also previous blog entry on Merck’s hypercholesterolemia efforts; link to press release, here).

The technology to which Tekmira acquired a worldwide exclusive license is referred to by Halo-Bio as multi-valent RNAs (mv-RNAs). It is a molecule that in its basic manifestation consists of three separate double-stranded regions, forming a structure similar to a Mercedes star. The RNAi machinery is thought to use each strand as a guide for the targeting of the same or, more interestingly, separate and independent genes.

Data from this technology is yet to emerge, although I would imagine that Tekmira has carefully evaluated mv-RNAs and various other RNAi trigger options before signing this deal given its increasing hints that it is looking at non-Alnylam RNAi triggers. It has become apparent that RNA interference is a robust naturally occurring process that it can harness various RNA molecules as substrates for efficient gene silencing. Of course, not all of them are created equal. Also worth noting in this context is that efficient RNAi largely depends on the 5’ end of the guide strand so that the 3’ end can function to satisfy complementarity requirements such as those for the formation of mv-RNAs.

Besides potency, additional practical and scientific questions remain to be answered. For example, the use of 3 RNA strands to generate one RNAi trigger may increase cost and quality. On the other hand, for those that follow the Tuschl II patent prosecutions in more detail or have seen the somewhat boring, yet useful study by Roche on the purity of annealed siRNAs, it should have occurred to a number of folks in the industry that strand annealing may not be the only way to generate double-stranded RNAs. Furthermore, even when using three strands (one and two may also be possible), the actual complexity may actually decrease compared to using 3 traditional RNAi triggers with 6 individual strands for targeting the same number of genes. Another question would be whether and which mv-RNAs are loaded directly into the RNAi RISC complex, or whether they require prior processing by other nucleases.

mv-RNAs may also have particular utility in lipo- and polyplex settings, or facilitate formulation of SNALP liposomes, because of their increased negative charge.

Of course, this deal also has to be seen in the context of the Tekmira-Alnylam feud. First of all, it is worth noting that Tekmira stated that mv-RNAs are an attractive alternative for multi-targeting RNAi Therapeutics. It still has the more traditional RNAi trigger options from Alnylam which, not least due to their simplicity, appear preferable over mv-RNAs for single-targeting applications.

The transaction also increases Tekmira's business development freedom from Alnylam. Due to the structural differentiation of mv-RNAs from traditional RNAi triggers, it is possible that certain of Alnylam's exclusive rights to Tekmira technology do not apply. In addition, mv-RNAs may also be sub-licensed independent of Tekmira's delivery technology.


Alnylam faces RNAi trigger uphill battle- even 3’ overhangs not safe

The worth of Alnylam’s RNAi trigger IP has deterioriated raplidly over the last two years and Tekmira may not require Alnylam IP even when using Tuschl siRNAs.

While Alnylam once had a decent shot at coming out as gate-keeping with Kreutzer-Limmer and Tuschl-I, failing in those patent prosecutions yet clinging on to ageing technology has meant that it failed to participate in RNAi trigger innovation, even if not gate-keeping. Anybody still remember Commodore or Atari or holds shares in Nokia and Research in Motion?

[correction 8/26/2011: I have re-read my entry and would like to clarify that Tuschl siRNAs are not 'out-dated' technology; it is more the underlying IP strategy that is failing].

Even as Max Planck, UMass, MIT, and Alnylam have just agreed to re-coordinate their Tuschl patent prosecution in the US, it is clear that the double-patenting issue was not the only issue preventing a strong Tuschl II from issuing. For example, by arguing that 3’ overhangs were implicit in T-I, yet T-I cannot claim this since it failed to recognize it, or by claiming 3' overhangs being obvious over other research on the discovery of Dicer in RNAi, the USPTO may have it both ways: deny a therapeutically useful T-I, yet reject T-II over obviousness involving T-I.

The T-II patents that have issued in the US are not that strong as they involve methods of synthesizing two RNA strands and annealing them to form double-stranded RNAs with 3’ overhangs. It is somewhat surprising that such a annealing method would have been granted a patent, and there are signs that the patent offices are starting to realize this.


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8 comments:

Anonymous said...

Interesting development, a couple of questions:
1. Do T1/2 apply to these composite triggers - do the individual fused strands/elements still contain T1/2 attributable features?
2. Although fusing three triggers together sounds efficacious, would the fusion of these three triggers together not cause three dimensional geospatial problems with targeting three different regions of the mRNA. In effect could you end up with a situation where the first target encountered is silenced but then the next locus cannot be accessed effectively?

Dirk Haussecker said...

1. No. One of the reasons why T1/2 don't apply (even if they issued in a stronger manner) is the shorter double-stranded region of Halo's mv-RNAs.

2.Not sure whether I understand you correctly, but any crowding/competition effect etc should not be much different from the use of 3 separate Tuschl-type siRNAs.

Anonymous said...

Thanks for your answer. With regard to 2 I meant: does the trigger on the spoke of your mercedes benz not have to bind to the host RNA? If so once bound does that not restrict the ability of the other fixed spokes to bind to areas of RNA that may not be in the immediate vicinity. 3 independent strands would not be restricted in this fashion. Not sure if I conveyed clearly enough!

Dirk Haussecker said...

I understand your question now. The answer is 'no', since the strand that interacts with the target mRNA will have been unwound and separated from the Mercedes star structure. It is unclear, however, what happens to the other 2 strands once the first one has been removed.

Anonymous said...

I am confused about your statement that part of the defense of T II is that the 3' overhang was obvious in the T I patent application. I thought that the defense of T II was dependent on the fact that the 3' overhang was not obvious in the T I patent application. Can you clarify?

Dirk Haussecker said...

I don't think I stated that. Please re-read. It is the USPTO that has argued that the 3' overhangs were implicit in T-I.

Anonymous said...

OT: when can we start hearing about alny and tkmr litigation outcome? this is dragging down TKMR.

Anonymous said...

MV-RNAi? Um, ok. With a few more of these moves Tekmira might become the new MDRNA.

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