Biotech Tracker News - SIRNA Drugs are Promising as Research Gains Traction
March 26, 2003 RNA interference, mediated in human cells by small interfering RNA (siRNA), is a hot topic with biotech companies. The technology, which is potentially a major improvement on antisense technologies, is already being used extensively in target validation efforts. Several companies are now focusing their efforts on applying the new technology to develop siRNA-based drugs. Similar to antisense, siRNA can block the production of a specific protein within cells by interfering with the messenger RNA (mRNA) encoding that protein. siRNA has the potential to be pharmacologically superior to antisense because much lower concentrations of the compounds are required to maintain an analogous biological effect. siRNA effects are also reported to last longer and have even higher specificity than antisense. siRNA emerged only recently, following the discovery in 2001 that RNA interference mechanisms function in mammalian cells as well as in flies and worms. Since then, new companies have been founded that take advantage of siRNA technology, and several existing companies have refocused their efforts on siRNA. The major players gathered in San Diego this week at the Strategic Research Institute’s siRNA conference.  Data presented at the conference show that good progress has been made in learning how to make effective siRNA reagents. The presentations also highlighted the major hurdles that remain, the most prominent of which is figuring out how to deliver short RNA sequences into target cells in people. Major players – namely private company Alnylam and RPI (NASDAQ: RZYM) – emerged.  Most of the participants at the meeting agreed that siRNA is superior to antisense in terms of experimental efficacy, duration of action, and specificity. Amgen (NASDAQ: AMGN) gave a particularly strong presentation on the virtues of siRNA versus antisense in its research efforts. Most target validation efforts, from big pharma research to academic labs, have already shifted away from antisense and towards siRNA. The one voice for antisense was, as might be expected, Isis (NASDAQ: ISIS). But even Isis’s presentation, which showed equivalent messenger RNA inhibition, stability, and duration of action between its advanced antisense chemistries and siRNA, highlights the fact that, in one year, siRNA has caught up with 15 years of antisense research.  Major progress has been made in the area of designing siRNA molecules. Two approaches were covered. First, algorithms for predicting functional sequences were developed by companies such as Dharmacon (privately held) and Amgen. Second, brute force approaches from companies like Qiagen (NASDAQ: QGENF) and a collaborative effort between Ambion (privately held) and Cenix (privately held) are underway to identify functional siRNA reagents that correspond to every human gene. One of these approaches, or perhaps a combination, will soon make identification of good siRNA reagents easy.  The more difficult hurdle to making siRNA drugs will be finding a way to get the molecules inside of cells in a patient. In cell lines, siRNA is loaded using lipid-based or other transfection reagents. In some mouse models, researchers have found that “hydrodynamics” is effective. (This is just a fancy way of saying that they double the blood volume of the mouse by injecting 2 mL of saline into the tail vein.) Delivery improvements are needed for human siRNA therapeutics.  Alnylam, founded last year, is working hard on novel delivery mechanisms, testing different lipid, peptide, vitamin, polymer, nanoparticle, and other siRNA conjugates. Its academic approach stems from its strong scientific founders, which include Nobel laureate Phil Sharp.  Perhaps even more impressive than Alnylam was RPI. Formerly known as Ribozyme Pharmaceuticals, RPI has completely shifted its focus from ribozyme-based therapeutics to developing siRNA drugs (although RPI’s ribozyme drug Angiozyme remains in phase II trials). Using its expertise in RNA modification, RPI has already developed chemical modifications that increase the half-life of siRNA in the body by over 100-fold. The company hopes that this stability will translate into efficacy, planning to first develop siRNA drugs to treat Hepatitis C infection as well as anti-VEGF constructs to treat macular degeneration. RPI hopes to have its first siRNA enter clinical development by early 2005.  Besides Alnylam and RPI, other companies working on developing siRNA drugs include Mirus (privately held), Ribopharma (privately held), and Benitec (Australia: BLT).  The hype over siRNA is reminiscent of that surrounding proteomics two years ago. Like proteomics and all new biotechnologies, siRNA will take a long time to translate into new drugs. Even if development moves quickly, we are still ten years away from approved siRNA-based drugs. Nevertheless, technological hurdles seem tractable, and the promise of siRNA therapeutics is vast.
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