Jump to content

drafter

Member
  • Posts

    1266
  • Joined

  • Last visited

drafter's Achievements

Newbie

Newbie (1/14)

0

Reputation

  1. drafter

    BLT

    Im hoping viral load in the tt034 as well as the calimmune patients is what's changed plastic, but after today's aloof message from the chairman i'm not sure it'd be shared with us retail holders when it matters.
  2. drafter

    BLT

    Plastic - i think fair to say the Americans are finally here!
  3. drafter

    BLT

    berkhout's latest paper rnai against HIV. if you haven't been following the CoH trial properly, watch John Rossi's Benitec / HIV video on youtube, then read berkhout's concluding paragraphs. berkhout_RNAi_HIV_251012.pdf
  4. drafter

    BLT

    Here's Dirk's thoughts on ISIS paper - in a nutshell he pretty much thinks it's a pile of the steamy brown stuff. Sunday, September 2, 2012 ISIS ssRNAi Challenge to Gold Standard RNAi Delivery Comes up Short ><http://2.bp.blogspot.com/-lVcduFwNvQY/UEO-O4RVViI/AAAAAAAABXE/8jN4KPRxUeU/s1600/Untitled-1%20copy.jpg The esteemed editors and reviewers of CELL got it wrong this time. Usually, when a high-impact journal like CELL decides to publish back-to-back papers on a given topic, it believes that they mark a turning point of some sort that will be cited all over. In this case (Lima et al.; Yu et al.), the turning point would be nanoparticle, or more precisely SNALP-formulated RNAi delivery 'out', and unformulated, single-stranded RNAi 'in'. For those new to my blog: it is the double-strand feature that is a defining property of the RNAi mechanism. While a single-stranded intermediate is generated in the process, numerous studies, including indeed the one by Lima et al., show that these are contrived, and consequently about 100-fold less potent 'inducers' of RNAi gene silencing. It is therefore surprising that CELL would publish a confirmation of this. What is new though is that the in vivo ssRNAi data involved unformulated ssRNAi application, will previous in vivo ssRNAi work by e.g. Merck involved LNP-mediated delivery (Haringsma et al., 2012; also covered on this blog here), but as detailed below, the efficacy was not impressive. To me, the main point of interest related to chemistry and how this sheds light on the basic RNAi mechanism, which actually made this paper enjoyable to read. For example, the metabolically stable 5'-(E)-vinylphosphonate modification and the positive effect of 2'F on Ago binding. Nevertheless, such biochemical detail is not the groundbreaking stuff that lands you a paper in CELL, but more something for the dedicated aficionado. Does ISIS feel threatened by SNALP delivery? The complexity of SNALP delivery, by which actually the difficulty of re-engineering SNALP technology without access to Tekmira's trade secrets and know-how is meant, is held against the technology also in a commercially competitive sense. If patient outcomes is the main goal, as long as you master complexity, isn't that a good thing, especially in terms of the all-important length of market exclusivity (note that the main cost of SNALP delivery is still the siRNA ingredient)? A common criticism of my writings is that I connect all things to Tekmira's SNALP technology. But read the Lima et al. paper and see for yourself how ISIS equates formulated RNAi delivery with liposomal delivery (start of the abstract e.g.): 'The therapeutic utility of siRNAs is limited by the requirement for complex formulations to deliver them to tissues. If potent single-stranded RNAs could be identified, they would provide a simpler path to pharmacological agents. Here, we describe single-stranded siRNAs (ss-siRNAs) that silence gene expression in animals absent lipid formulation.' Or 'However, in their current state, the therapeutic utility of siRNA is limited by the requirement for complex lipid formulations to deliver siRNA to peripheral tissues (Vaishnaw et al., 2010).' It looks like 1-billion market cap ISIS feels threatened by $40M market cap Tekmira's SNALP technology after all and is a very interested participant in the frivolous patent infringement lawsuit against Tekmira (frivolous for the reason alone that Alnylam expressly congratulated Tekmira on the BMS deal). SNALP requires 1000-10.000-fold less oligonucleotides The assessment that the ssRNAi work by ISIS does not mark a turning point in systemic RNAi delivery is based on simple math. 1000 to 10.000-fold higher amounts of oligonucleotides were required to achieve equivalent knockdowns in mice: conservative 50microgram/kg/month for SNALP vs 50mg/kg/twice a week for ISIS ssRNAi. As with any drug, large doses increase the risk of causing toxicities. In this case, it is particularly the accumulations of large amounts of phosphorothioated oligonucleotides in the liver and kidney that causes such concern. Of course, SNALP LNP delivery is not entirely without its safety issues. For example, in the clinic it still involves the use of transient immune suppression which may e.g. be prohibitive to their use in millions of patients with less severe forms of hypercholesterolemia. Although assuming for a moment that the amount of required oligonucleotides should be irrelevant as long as it was safe, antisense technologies still suffer from poor cost of goods. Last week for example, the CEO of another antisense company, Sarepta Therapeutics (formerly known as AVI Biopharma), wrote in an unsettling Open Letter to the Duchenne Muscular Dystrophy community that the company essentially cannot afford the large, almost nutritional amounts of oligonucleotides that are required for attempting a therapeutic splice correction. Closer to home, instead of acknowledging their current cost of goods, ISIS Pharmaceuticals is only providing estimates for their future oligo manufacturing cost goals. Extrahepatic tissues, which ones please? Another claim by ISIS related to their ssRNAi tech was that it would be applicable beyond the liver ('broadly distributed and active in multiple organs'), also following systemic administration. However, once again, this was directly contradicted by their own data which showed a maximally 35% knockdown (the type of from 100 to 65, not from 100 to 35 mind you) for such a tissue (the kidney) when administering…100mg/kg of oligonucleotides of mice. The accompanying Huntington's Disease paper achieved ssRNAi-mediated knockdown in the brain. This, however, was observed following non-systemic, intraventricular infusion of large amounts of oligonucleotides in small mice brains. Alnylam was right in terminating ssRNAi collaboration Taken together, the publications explain why Alnylam decided two years ago to terminate their ssRNAi collaboration with ISIS. In addition to using Tekmira's intravenously infused SNALP LNPs, Alnylam has been working on GalNAc-siRNA conjugates as a subcutaneously deliverable alternative for gene knockdown in the liver. Although the gene knockdown achievable with that technology still pales in comparison to SNALP LNP, it is about 10-fold more potent than ISIS' ssRNAi, which goes to show that despite the disadvantages in cellular delivery of unformulated, rigid dsRNAs, their dramatically increased potency more than compensates for it. At least Lima and colleagues and I agree on this point (opening statement of the introduction): 'RNA interference (RNAi) is a mechanism by which double-stranded RNA triggers the loss of homologous sequence (Fire et al., 1998).' [Emphasis mine] </h2>
  5. drafter

    BLT

    i reckon Stanley still has RNAi envy, but now starting to smell a little of desparation. That's why he's trying to re-badge his old moudly IP with a shiny new RNAi like cover. But he's being misleading and sneaky as is the norm for this guy - RNAi delivery difficulties is yesterday's news. They've cracked that nut, if the reporters bothered to do their research. And the impotency problem for antisense is still there, unless you want to swallow a bucket of the stuff. and what happened to his claims that ISIS IP owns RNAi? He's dropped that cause it's bollocks, is probably still running interference on the side, and knows he is fast running out of time before the engines fire in both siRNA and shRNA forms of RNAi therapy. Once they light up, the snail paced ISIS tech is going to be very sub standard, and ISIS will need to dig into their cash pile and pay through the nose for RNAi IP just to keep up. just the way i see it.
  6. drafter

    BLT

    Plastic, Ognid sends his regards from HC. Cheers, Drafter (so you're therefore not off the hook on those....was it mojitos?)
  7. drafter

    BLT

    nice one plastic. i'll keep my powder dry sunday. as for benitec, any spare change coming my way will be going toward it whilst it allows me to average down. That said, i'd be happy buying up to 20c right now if the market wants to go there. but we know the market won't budge until they get it in writing.
  8. drafter

    BLT

    not much i suspect. whilst Alny are busy trying to hold their IP together, get siRNA delivery going, and debase other siRNA players and TKM, ddRNAi has just gone straight past the whole siRNA field in the clinic. And doesn't look like slowing down any time soon.
  9. drafter

    BLT

    haha - close Plastic. I'm in a bike race on the 4th.
  10. drafter

    BLT

    aerospace sector?! - maybe after they land a ~$300M deal for say the pain therapeutic and share price goes into orbit
  11. drafter

    BLT

    new study paper from Pfizer regarding the Tacere HCV / TT-034 programme attached (less diagrams so i could get it to upload). note in reference section reference number 35. Pfizer_HCV_Paper_271211.pdf
  12. drafter

    BLT

    actually it's blt that are on my payroll - and i'd be disappointed not to see a return because the science is promising and the ip secured. blt management the other big part of the equation - to date i'm impressed with the strategy being rolled out by Peter French. It's a biotech so I'm prepared of course to play it with a longer timeframe. It's also a specky so i can live without the cash should heaven forbid your prediction of it being the world's biggest con be true (i doubt it), or should it get a legal buffeting again instigated by less than useful folk such as towarnicki (also less than likely nowdays).
  13. drafter

    BLT

    i take it nothing more detail than big pharma anything but finished with RNAi space and all that it entails. anti-sense may find it's place too but it'll be a horses for courses approach. astonishing turn around of biopress sentiment toward RNAi underway
  14. drafter

    BLT

    anyone able to get the full article open on this? http://www.genomeweb.com/rnai/rnai-efforts...c-one-two-years
  15. drafter

    BLT

    well it does - because it will take money to flow before anyone would want to make any transaction, and big pharma won't talk serious until delivery cracked. there a lot of interdependencies, direct and indirect. For the next couple of years at least if not more what's good for Alny is good for Benitec, and good for RNAi. Consider them the Collingwood Football Club of RNAi. if the promise of ddRNAi therapeutics was safely tucked behind a big seemingly impenetrable wall, lately that wall has developed some significant structural cracks. i put this on HC and worth copying it here as very likely this news will impact benitec for the better over the next year or two The Burrill Report (November 28, 2011): Will Alnylam Results Reignite Fervor for RNAi (.MP3,12.74 Mb)
×
×
  • Create New...