RNAi: Seeking a Cure at the Flick of a Switch 
By Alex Frumin | August 2, 2007A promising biotech breakthrough is coming that will bring with it hopes of a cure for the most notorious diseases, and in its wake will leave its investors with greater health and greater wealth.
Suppose that you’ve been feeling a constant discomfort in your abdomen and just to be cautious, you decide to go to your personal physician for a checkup. A bunch of tests, a second opinion, and few days later you find out the worst. Just like over 10 million men, women, and children, you have been diagnosed with some type of cancer (US National Cancer Institute, 2002). Depending on how advanced your case may be, your choices are chemotherapy, radiation, or surgery; probably leaving your body bruised, exhausted, and badly damaged. Even after the painful ordeal of treatment, the chances of survival may still be poor. But wait! Instead, you doctor turns to you, looks you straight in the eye with a slight smirk on his face, and says: “No worries, we now have a cure. It’s as easy as flicking off a light switch.”
From Big Pharma to Small Biotech, that light switch is being sought after in the new research craze called RNAi (also known as RNA-mediated interference). Termed that way by Craig C. Mello and Andrew Fire in their 1998 Nature paper, for which in 2006 they received the Nobel Prize in Physiology or Medicine, RNAi exploits a cell’s normal mechanism of gene expression. Trying to spare you from a detailed lesson in molecular biology and biochemistry, I will tell you where the story begins: Every cell in our body contains DNA in its nucleus, where vast archives of instructions are stored for use in the development and functioning of all known living organisms. But DNA can never leave the nucleus for stability reasons, and this is where RNA comes in. DNA is transcribed into single stranded RNA, or mRNA (messenger RNA), and that mRNA is exported out of the nucleus into the cell’s cytoplasm, all containing that same chemical recipe that it obtained from its cousin DNA. Cellular structures called ribosomes now come in and translate the mRNA into protein, and as we all know, proteins are the building blocks of all cells in the organism.
Now, when a virus attacks a cell, it introduces its own RNA into the cell and forces the cell to use its own mechanism of translation to make multiple copies of viral RNA and viral proteins. But when the virus is copying itself, it is double stranded, unlike the single stranded mRNA of the cell. The process of RNAi uses this distinction to search out the double stranded RNA and chop them up into small pieces using an enzyme nicknamed Dicer, forming siRNA (small interfering RNA). Then proteins called RISC (RNA induced silencing) unwind that viral RNA, pick up one of the strands, and go in search of matching sequences that may still be in the cell. As it finds matches, it binds to that viral RNA strand and blocks the viral RNA protein production; hence, halting the virus in its attack.
Ok, so what can we do with this you ask? Well contemplate this: What if we artificially introduce a double stranded RNA from a diseased gene into a cell? Theoretically, the cell’s normal RNAi process should silence that gene just as it would silence a naturally invading virus. From petri-dishes, to lab animals, to first human volunteers in late 2004, researches have been trying to figure out radical new ways to manipulate a patient’s own RNAi immune response to fight hundreds of diseases. Visualize that just by turning off a gene like a light switch, illnesses as severe and debilitating as macular degeneration, respiratory infections, hepatitis, Huntington’s disease, Alzheimer’s, HIV, and yes, even cancer, could be shut off from progressing.
Some of the names that are known to be working with this technology include the big boys of Big Pharma: Novartis (NVS) and its collaboration with Alnylam (ALNY), not to mention Alnylam’s own federal government contract; Merck (MRK) and its partnership with Alnylam and acquisition of Sirna Therapeutic for $1.1 billion; Pfizer (PFE) and Quark Biotech Inc’s licensing agreement for RTP-801; AstraZeneca (AZN) and Britain’s Silence Therapeutics $400 million research pact; Roche (RHHBF.PK) and its last month announcement of a major alliance with Alnylam worth $331 million plus; and Bristol-Myers Squibb’s (BMY) payment of $192 million to Isis Pharmaceutical (ISIS) for exclusive access to its PCSK9 research program. The smaller Isis Pharmaceuticals, one of the first pioneers in RNAi drugs, and biotech CytRx Corp (CYTR) even have separate divisions devoted solely to siRNA chemistry and formulation, with other companies like Nastech (NSTK) licensing intellectual property and technology for their own research and development.
The next few years will start to tell the story of whether this amazing innovation can succeed clinically. Though RNAi research is still in its infancy, as there are still many hurdles on the horizon, I believe that the sun has only begun to rise into the clear blue sky of RNAi.
DISCLOSURE: The author of this article has a long position in AZN and is an employee of Roche | |