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Demonstrated “gene silencing” in humans via siRNA administration

March 25, 2010

From Nature:

Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approximately 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response. We are at present conducting the first in-human phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumour biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amounts that correlate with dose levels of the nanoparticles administered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a reduction was found in both the specific messenger RNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (reduction in mRNA and protein) by an RNAi mechanism of action.

[Davis ME, Zuckerman JE, Choi CH, et. al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature (In Press)]

RNA interference is a very new field of research. The guys who first observed RNAi won the Nobel Prize just 4 years ago.

From Calando Pharmaceuticals’ press release:

Thus far in the trial, no significant drug-related toxicities, known as serious adverse events (SAEs), have been observed that may limit use.

Their Phase I trial appeared to only have 3 subjects but this is promising news. From a Nature Review in 2009, other clinical trials are ongoing using RNAi-based therapeutics:

[Castanotto D, Rossi JJ. The promises and pitfalls of RNA-interference-based therapeutics. Nature. 2009;457(7228):426-33.]

ARWR is up 100% since this announcement. Seems like it should be more like 1000%. I guess dull investors are spooked by Obongo-care.

3 Comments leave one →
  1. March 25, 2010 1:45 pm

    I used to own ARWR and TINY back when I was a more naive investor.

    • March 25, 2010 10:19 pm

      I was hoping you would comment on this.

      I know nothing about pharmaceuticals, so you’re gonna have to explain why this is a bad deal. I realize they probably won’t turn a profit for a least a decade or so, but it seems like they could get a very favorable buyout from a much larger company as the trials continue.

      • March 26, 2010 4:56 pm

        Development stage “research” companies like ARWR are just a way for the big boys to offshore their R&D by having it paid for by the investing public through mutual funds and gullible retailers. They print out shares like nobodies business until nobody wants to buy anymore. The best ones will eventually get bought, but betting on that is like rolling the dice. (You could buy at 4 bucks, it drops to 1, then gets bought at 2. Sure, those who bought at 1 made money, but…. And I think ARWR will have to do a RS to stay listed. not good.) Unless you have insider knowledge, betting on these things is a suckers game, although it can be fun to put chump change in a few very speculative securities like this (but trust me, you’ll eventually tire of that).

        When investing, go primarily for solidly profitable companies with little debt. Then pick those with the best growth prospects. Value before growth – but both are important. You may read in a few stupid books that value and growth investing are mutually exclusive, but they’re not – you just have to be more patient.

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