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Alnylam Pharmaceuticals, Inc. Message Board

  • robertvince robertvince Aug 10, 2012 10:51 AM Flag

    Is RNAi Making a Comeback? Part 1

    From Doug Casey's research team:
    We know that we (and all living systems) inherit our genetic traits through a naturally occurring information storage system known as deoxyribonucleic acid, or DNA. DNA consists of a linear sequence of the chemical bases adenine, cytosine, guanine, and thymine (denoted by the symbols A, C, G, and T), attached to a repeating linear chain made up of alternating sugar and phosphate segments and bound together with hydrogen bonds in a double helix to complementary bases. The "A" of one strand always forms a base pair with the "T" of the other strand, and "C" always forms a base pair with "G."

    Our molecular blueprint for life, the haploid human genome, comprises approximately three billion DNA base pairs, divided into 23 pairs of chromosomes ranging in size from about 50 million to 250 million bases. Contained within these chromosomes are approximately 23,000 smaller regions, called genes, each one containing the recipe for a protein or group of related proteins that are produced in a linear, step-by-step process.

    First (and we've simplified things here), in transcription, an enzyme called RNA polymerase converts the DNA strand base for base into messenger RNA (mRNA). The mRNA has the same sequence as the DNA, except that thymine (T) is replaced with uracil (U). The mRNA then carries the information out of the cell nucleus into the cytoplasm for the second step in protein production, called translation.

    Once in the cytoplasm, the mRNA interacts with a specialized complex called a ribosome, which "reads" the sequence of mRNA bases and translates them into proteins. These proteins go on to play key roles in the structure and function of all cells, including the regulation and execution of subsequent transcription and translation.

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    • This flow of information from DNA to RNA to proteins is one of the fundamental principles of molecular biology - so important that it is sometimes called the "central dogma."

      The important takeaway for our purposes is that DNA itself is trapped in the cell nucleus. It's RNA's job to get the information out of the nucleus and into the cytoplasm, transforming you from a chemical recipe to a real living, breathing human. Because of RNA we can build proteins. We are made of proteins. In other words, RNA builds life. And that's big.

      But there is something else amazing about RNA that could revolutionize how doctors treat many (if not most) chronic human diseases. And nobody knew about it until just a few years ago.

      Back in 1986, a geneticist named Rich Jorgensen was working at a small biotech startup in California. He was tasked with creating a spectacular new flower, to help attract venture capital funding for the company. His plan was to create a very, very purple petunia. So he inserted an extra copy of the purple-producing gene into the plant's DNA. But instead of producing purple, Jorgensen's petunia instead bloomed with white flowers, the complete opposite of what the scientist expected. Inserting the extra purple-producing gene had resulted in the flowers completely losing their pigmentation. This was a big puzzle. And it took another decade of scientific research (and countless experiments with flowers, fruit flies, worms, and other organisms) to figure out what was going on.

      Completely by accident, Jorgensen had stumbled upon an ancient secret inside living cells - a process that cells use to turn down, or silence, the activity of specific genes. This process is now known as RNA interference, or RNAi.

      RNAi is thought to have evolved about a billion years ago, as a cellular defense mechanism against invaders such as RNA viruses and to combat the spread of harmful, mutation-causing genetic elements called transposons, within a cell's DNA. It works by destroying the messenger (mRNAs) carrying genetic information to the cell's protein factories. By killing the mRNAs and not allowing the protein specified by that gene to be made, the gene is rendered essentially inactive.

      When Jorgensen inserted the extra purple-producing gene into the petunia's DNA, it triggered the cell's RNAi to silence all the purple-producing genes because the cell thought the recipe for the protein looked fishy. Exactly why the cell thought this is a bit too complex to go into here. But in very simple terms, the instructions Jorgensen inserted to make more purple happened to have a suspicious viral shape.

      • 1 Reply to robertvince
      • What's important is that with RNAi, scientists had discovered a way to effectively silence genes one at a time (by shutting down the protein-building process), just based on knowing their sequence. Since many, if not most, chronic human diseases result from inappropriate protein production or improper protein activity, the implications for the treatment of disease were profound. Cancer, HIV and other infectious diseases, neurodegenerative disorders, and cardiovascular and cerebrovascular diseases - all became theoretical fair game for treatment with RNAi therapeutics.

        And so, not too long after the discovery of RNAi in 1998 - by Craig Mello and Andrew Fire (who were awarded the 2006 Nobel Prize in physiology or medicine for the discovery) - came the hype. Drugs based on RNAi were said to be the next major class of human therapeutics. Big pharma and small biotech firms alike pumped a flood of money into RNAi-based drug development.

        The boom phase in RNAi got rolling in 2005 and lasted through about 2008. During that time we saw a bidding war break out for access to potentially gate-keeping RNAi intellectual property and several billion dollars in investments in the space by big pharma. Merck paid $1.1 billion to acquire Sirna Therapeutics, and Roche paid more than $300 million for a limited platform license from Alnylam (arguably the global leader when it comes to RNAi IP). The industry loved the attention, and the media fanned the flames. Consequently, unrealistic expectations set in, and investors fell prey to the mistaken notion that the technical barriers to exploiting RNAi in medicine were relatively low.

        The industry was in for a wake-up call, however, when the difficulty surrounding RNAi drug delivery came to light. The drugs (comprised of what's called small interfering RNA, or "siRNA") break down quickly in the bloodstream; and even if they reach the cells in the body where they are needed, they have trouble entering the cells. Once the mistake of putting IP ahead of enablement was recognized a backlash ensued, and there was a severe crisis of confidence in the potential of RNAi thereapeutics. Novartis ended its five-year partnership with Alnylam in September 2010. Shortly thereafter, Roche, one of the world's biggest spenders on drug R&D, terminated its RNAi program altogether. Stock prices of companies operating in the space plummeted.

        Just recently, however, we've started to see a comeback in RNAi. The recovery is based not on hype, but on sound science and clinical successes, which should pique investors' interest. Technical hurdles remain but are being overcome, and companies are advancing drug candidates in the clinic. Alnylam, for example, now has four RNAi drugs in clinical trials and is on pace to have five RNAi therapeutic programs in advanced clinical development by 2015. Together with collaborators at MIT, the company also recently announced the discovery of "core-shell" nanoparticles that have optimal chemical and physical properties for effective, systemic intracellular delivery of RNAi therapeutics. The findings were published in the Proceedings of the National Academy of Sciences. And Alnylam is by no means the only one making advances in the RNAi space.

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