| I rarely give stock advice. The last time I did was in | | | | mechanism of gene regulation in all cells, accelerated |
| the summer of 1964 when I read in the newspaper | | | | understanding of how RNAi works. SiRNA is an |
| that a new company called ComSat was having an | | | | exogenous synthetic version of the natural |
| IPO in September. I considered this, perhaps naively, | | | | endogenous microRNA that takes advantage of the |
| a sure thing. Yet being in my first job I had no | | | | cellular machinery that normally processes and |
| money to invest. So, I decided to watch this stock | | | | mediates the function of microRNA. Micro- or siRNA |
| with the fantasy of having invested $1,000 ($6,548 in | | | | (RNAi) is targeted to inhibit a specific counterpart |
| today's dollars). My plan was to buy at the IPO price | | | | transcript (messenger RNA) that serves as a |
| of $10 a share and then sell just before the launch of | | | | template for synthesis of an individual protein, the |
| the first commercial communications satellite, just in | | | | natural process of gene expression. RNAi is |
| case the launch failed. The stock rose meteorically | | | | processed by a ribonuclease enzyme that binds to a |
| from $10 per share to $80 (the launch did not fail), | | | | larger precursor siRNA. The enzyme processes siRNA |
| then the stock split and rose again to more than $80 | | | | into a 21-nucleotide base-pair double stranded |
| per share. I made about $240,000 from my $1,000 | | | | molecule. The specificity of RNAi is governed both by |
| fantasy investment, equivalent to $1.5 million today. | | | | its 'complimentarity' to a particular messenger RNA |
| The reason I bring this up is that recently, I was | | | | nucleic acid sequence and also by a complex of |
| fortunate to attend a small meeting in Boston that | | | | proteins whose function is to mediate the binding of |
| focused on developments in the seemingly esoteric | | | | the RNAi to a target sequence on the messenger |
| field of siRNA or "short interfering RNA" used to | | | | RNA, usually in the 3'-noncoding region of the |
| silence genes. The promise of this technology has | | | | messenger RNA. This binding event leads to a |
| rightfully created a significant buzz in the scientific and | | | | shut-down in synthesis of the protein encoded by |
| investment communities over for the last two to | | | | the messenger RNA (called "knock-down"). |
| three years. And as I left this meeting, it occurred to | | | | There is currently little mystery about how to design |
| me that in the next 10 to 20 years, siRNA, also called | | | | siRNA molecules and synthesize them, as this method |
| "RNAi", will probably dominate drug development, with | | | | is aided by readily available algorithms. In fact, Todd |
| many successful drugs currently targeting specific | | | | Woolf, CEO & President of RXi Pharmaceuticals, |
| proteins, like Genentech's Herceptin and Imclone's | | | | says, "Weeks instead of years to lead compounds." |
| Erbitux, being replaced by RNAi-based drugs. | | | | This finely tunable technique of RNAi knock-down is |
| Furthermore, many disease-causing proteins thought | | | | also currently used in many academic research labs. |
| to be "undrugable", like the metastatic biomarker | | | | Finally, many studies have been completed including |
| L-plastin for colon, breast, melanoma, prostate, and | | | | Phase I clinical trials that indicate the siRNA is |
| bladder cancer, could now be targeted by RNAi | | | | essentially non-toxic. Conventional drugs have always |
| drugs. | | | | required the balancing of efficacious doses with |
| Andrew Fire, of Stanford, and Craig Mello, at the | | | | consideration of the drug's negative side-effects. |
| University of Massachusetts, discovered "gene | | | | Several companies and labs have shown siRNA |
| silencing by double-stranded RNA" in 1998, earning | | | | conjugated with cholesterol or other lipid carriers will |
| them the 2006 Nobel Prize in Medicine. In 2001 | | | | attach to cholesterol carrier proteins in the blood and |
| companies started forming around RNAi. One of | | | | transport to the liver rather than being excreted. If |
| them, Alnylam Pharmaceuticals filed its S-1 registration | | | | an siRNA is used that knocks down an enzyme |
| with the SEC in February 2004, claiming $23,000 in | | | | involved in cholesterol production by the liver, then |
| cash assets and creating 3.2 million shares worth 28 | | | | serum cholesterol levels can be diminished in mice by |
| cents each. Two years later, Alnylam went public | | | | 30 to 40 percent without diminishing the good |
| with stock selling at $7.50 per share after an | | | | cholesterol (HDL) levels. The blockbuster statin drugs |
| unprecedented short start-up time. Alnylam's shares | | | | like Lipitor, which are well known to produce toxic |
| were selling on NASDAQ at around $16 per share in | | | | side-effects in the liver, also reduce cholesterol levels |
| early July after hitting a 52-week high of $24.46 last | | | | in the blood by about 30 to 40 percent. In the |
| December. By December or perhaps early winter, | | | | mouse model, the cholesterol-reducing effects of one |
| Alnylam will announce the outcome of its Phase II | | | | treatment with siRNA lasts three to four weeks. |
| clinical trial on their lead product for treating the infant | | | | In a mouse model for intestinal adenomatous |
| respiratory disease caused by Respiratory Syncytial | | | | polyposis, the mice develop a high density of benign |
| Virus (RSV infections). Alnylam has multiple | | | | polyps that ultimately block the intestines, |
| collaborations funded by Merck, and about 20 pipeline | | | | subsequently leading to death. In humans, such polyps |
| products. At the same time Merck bought Sirna | | | | are precursors to malignant colon cancer. Johannes |
| Therapeutics, another RNAi company with strong IP | | | | Fruehauf of Cequent Pharmaceuticals and Harvard |
| for this technology. During the last year, in order to | | | | Medical School described a novel method for |
| acquire additional RNAi-relevant IP, Hoffmann-La | | | | delivering siRNA to the intestinal tract which targeted |
| Roche bought 454, Sigma Chemicals bought Proligo, | | | | beta-catenin synthesized by polyp cells. Increased |
| Alnylam bought Ribopharma, Acuity Pharmaceuticals | | | | expression of beta-catenin is associated with |
| merged with two other companies to form Opko, | | | | proliferation of polyp cells but not by itself in the |
| Dharmacon became part of Thermo-Fisher Scientific, | | | | conversion of benign polyps to malignancy. Cequent |
| and RXi Pharmaceuticals was spawned by CytRx. | | | | has demonstrated that bacteria, such as E. coli, |
| Also Pfizer, GlaxoSmithKline, Novartis, Bristol-Myers | | | | carrying about 100 copies of recombinant siRNA in a |
| Squibb, and Abbott Labs have started R&D | | | | plasmid vector, can simply be fed to polyposis mice |
| programs around RNAi. | | | | whose intestines are clogged with polyps. |
| Santaris Pharma, a Danish company formed in 2003, | | | | Administration of these bacteria containing the siRNA |
| has a novel method for making and stabilizing RNAi | | | | copies killed the polyps and cleared up the problem |
| and drug products in Phase II clinical development. | | | | completely; the histopathology pictures established |
| Santaris is strategically partnered through licensing | | | | clearly that the intestines were cleansed of the |
| agreements with Enzon, a leading clinical research | | | | polyps. The explanation for this efficacy is that |
| organization that is conducting clinical trials in the U.S. | | | | thousands of these bacteria were engulfed by the |
| for many Santaris' drug candidates. Santaris has | | | | polyp cells by the natural process of endocytosis. |
| completed Phase I/II clinical trials in Denmark, France, | | | | The bacteria were dissolved in the endosomes, the |
| the U.K. and the U.S. for an RNAi drug for treating | | | | plasmids carrying the siRNA insert were fragmented, |
| chronic lymphocytic leukemia (CLL) and Phase I trials | | | | and the liberated siRNA inhibited beta-catenin |
| for a second product treating renal and colon | | | | synthesis in the polyps. This last step causes the |
| carcinoma and multiple myeloma. The CLL product | | | | polyps to self-destruct by the natural mechanism of |
| should compete favorably with Genta's BCL-2 | | | | apoptosis, or programmed cell death. |
| antisense (RNA) product in development for over a | | | | The prospect for siRNA as a therapy seems unlimited |
| decade, through phase III clinical development, and in | | | | in that any and every gene can become a target for |
| pre-registration for CLL and malignant melanoma. | | | | this therapy. Before siRNA, many potential disease |
| As an aside, it's worth noting that several of these | | | | targets were considered "undrugable," meaning that |
| companies are Nerac clients. | | | | virtually every disease can be considered for siRNA |
| RNAi therapy is not like stem cell therapy, which will | | | | therapy, including all forms of cancer, metabolic |
| take decades to develop. Approval of the first RNAi | | | | diseases like diabetes, and cardiovascular disease. One |
| drugs is expected in three to five years. This is | | | | speaker at the meeting predicted that when the first |
| because stem cell therapy is complex and the science | | | | siRNA proved its efficacy in a Phase III clinical trial, |
| is still in its infancy. By contrast RNAi is well | | | | this event would lead to an explosion of interest in |
| developed because of the advanced understanding | | | | siRNA by Big Pharma and the investment community. |
| of genetics and gene expression. In fact RNAi will be | | | | It seems inevitable that this will happen in the not |
| used to make stem cell therapy work. | | | | too distant future. |
| The 1993 discovery of microRNA, a natural | | | | |