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Isis Pharmaceuticals, Inc. Message Board

  • bertrand1234 Jan 14, 2013 2:35 PM Flag

    Biochemist's take on Isis' new siRNA tech

    I am reposting as a new topic since this should be pretty good info.

    I am a biochemist so I'm going to give you guys the rundown on the real impact of this paper.

    The journal article that describes this breakthrough (and it is truly a breakthrough in the scientific world) came out a couple months ago and I was astonished when I read about it. Aside from the fact that it was published in Nature, this is a truly amazing feat.

    There are 2 ways to degrade mRNA:
    1. use the RNaseH pathway (Isis' current antisense technology uses this) - antisense binds to the mRNA and causes RNaseH to degrade it, leading to no production of the corresponding protein.

    2. use the siRNA pathway (Ago2, dicer, etc) - this is sort of a redundant system where the "useful" strand enters a protein complex, scans all mRNA for the "match" and degrades it. The difference here is that the "useful" strand that is injected is not used up right away via 1:1 match. What that means is that one strand can cause the degradation of many of the same mRNA. That's one reason why this reduces the dose.

    For years, companies (including Alnylam) and research labs around the world have been trying to figure out how to successfully get siRNA into cells in animals because this is the most efficient system on a per molecule basis. Most of the attempts include using lipids (basically simple mini cells), nanoparticles, viruses and many other methods. The goal was to allow the siRNA to survive long enough in the bloodstream to be effective but to also have it delivered into cells. Although some of them are effective, they are normally pretty toxic to living systems and don't get enough siRNA into the cells (or none at all) to be effective.

    What Isis has done here is determined if you need both strands of the siRNA for activity (siRNA is double stranded like DNA) or if you can manage with just 1 strand with modifications. What they found is that you only need the "useful" strand and by using their modifications, you can get a relatively high amount of siRNA into cells. In essense the accomplished 2 important goals:

    1. simplified the delivery system - no need for secondary agents to help siRNA survive in the bloodstream and enter the cells. This reduces manufacturing cost of the final drug/delivery system

    2. Successfully showed activity - their siRNA is active and can be done at low doses

    Isis has achieved both goals; neither of which other companies and labs have not been able to achieve. So not only does Isis have a grapple on the antisense technology, this opens the door to using siRNA, which is significantly more efficient.

    In effect, they have opened the floor to a whole new platform. If I had the choice, any drugs that work with antisense, I would convert to siRNA technology since it can be done at lower doses and can extend the patent life of targets they already have.

    As a scientist...I cannot emphasize this enough...THIS IS A HUGE accomplishment. Analogous to being able to land astronauts on the moon. The possibilities after this discovery are immense.

    Sentiment: Strong Buy

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    • Thank you Bertrand. You were able to explain the science in layman's terms that can be understood by non-science background individuals like myself. You mention that "For years, companies (including Alnylam) and research labs around the world have been trying to figure out how to successfully get siRNA into cells in animals because this is the most efficient system on a per molecule basis. "
      Are you up to date on all the companies involved in this technology? Has ISIS achieved what no other company has to date? You also mention that because of this achievement is siRNA, ISIS can extend the patent life of targets they already have. My question is, is this ISIS breakthrough something that can not be easily worked around by other biotech companies involved in this technology? If not, can we ascertain that ISIS is at the forefront of siRNA applications?

      I appreciate any input you can provide with your expertise in the biochemistry industry.

      • 2 Replies to wanna_million
      • bertrand1234 Jan 15, 2013 12:22 PM Flag

        Thanks for the support. I actually still do work on siRNA delivery and am pretty familiar with the technologies out there right now. As far as I know, most companies/labs are still trying to get normal double stranded siRNA into cells. The majority (if not all) of them have not even thought of trying to deliver single stranded siRNA since it is even more susceptible to normal enzyme degradation. In other words, unless there was some unique way of modifying the single strand to prevent this, nobody in their right mind would even dream of trying. But Isis has the ability to do these unique chemical modifications and has succeeded. Getting a single strand of RNA to survive in the bloodstream is already an achievement in and of itself.

        Regarding your question about a workaround, I do not foresee a workaround being done by anybody else that quickly. Research is not something where you try something overnight and find out the results the next morning. A project of the scale this siRNA one was, it probably took them at least a few years to get enough robust data to feel comfortable about publishing it. In general, the bigger the breakthrough, the more you want to verify that it really is correct. Also, the fact that they have done animal studies already speaks volumes as to how far they have gone with this technology. Animal studies in themselves take several months at least to run the study and analyze the data. So unless another company and/or lab has the chemical prowess and innovation power, I do not see anyone else catching up anytime soon. There are probably other chemical modifications that will do the same thing or might even be better, but I assure you Isis is probably already looking for improvements.

      • Seems to me, if you achieve a first, the patent for it is a lock. Duh ?

        Sentiment: Strong Buy

    • Thank you for your concise explanation of the importance of these accomplishments.

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