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Replies to post #175146 on Biotech Values
Clinical progress could not have taken place without numerous research advances over the past decade. Serum stability has been improved through the introduction of new oligonucleotide chemistries, such as 2'-O-methyl (2'-O-Me) ribose groups, 2' fluoro-ß-D-arabinonucleotides or unlocked nucleic acids. Potency and off-target effects have been addressed through siRNA seed element design using algorithms (e.g., GC content, asymmetric thermostability, interaction scanning with 3' UTRs across the genome) or novel architectures (e.g., blunt 2'-O-Me RNA duplexes that reduce passenger strand loading into RISC). Similarly, increased understanding of the role of oligonucleotide length and GU-rich content in siRNA interactions with toll-like receptors 3, 7 and 8, RIG-I and PKR has reduced immunogenicity concerns.
But it is perhaps delivery where the greatest strides have been made. Refinements in Tekmira's small nucleic acid lipid particles have allowed companies like Alnylam to achieve 100- to 1,000-fold improvements in therapeutic index. Other platforms, such as neutrally charged polyconjugates (e.g., Arrowhead's DPC technology) or simple conjugates (e.g., Alnylam's trivalent N-acetyl galactosamine conjugates) also show promise, particularly for delivery to hepatocytes. Last month's formation of Voyager Therapeutics also raises the possibility that novel adeno-associated viral vectors may be combined with DNA-directed RNAi drugs to achieve the same goal. Startup Solstice Biologics is pioneering an alternative approach in which the siRNA backbone is directly modified with amidite chemistry to facilitate delivery (p. 229).
A big question surrounds the long-term toxicities of lipid nanoparticles. Thus far, these have mostly been used to enhance approved chemotherapies or fungicides, and these preparations have fairly toxic side effects, sometimes requiring administration of corticosteroids or antihistamines. Stringent oversight of the potential effects of these delivery agents on humans will likely be a major focus for regulators.
But there remains reason for optimism. Sanofi's option on Alnylam's siRNA clinical programs indicates that the era of investing in RNAi as a technology platform is coming to an end—the era of product-specific partnerships is beginning. The shift of many companies from a focus on heroic, last-ditch cancer treatments to drugs against potentially 'more tractable' rare diseases also indicates maturation. RNAi drugs represent an intriguing opportunity, enabling the modulation of targets undruggable by antibodies or small molecules, all with facile manufacture and short preclinical development times. So although this may not be a RNAissance, it certainly looks like a rally.
But now comes progress in the effort to build a system of quality control for gene editing. In the past two months, three academic groups have published papers—all in Nature Biotechnology—describing new ways to measure the frequency and location of off-target cuts in cells’ DNA. A review in this month’s issue covers all three papers, and the reviewers laud them for moving the field forward: “The new studies are a major step toward clinical applications of genome engineering as they show that sensitive, genome-scale detection of nuclease activity is now technically feasible.” (Nucleases are the “scissors” that gene editing systems use to cut DNA.)
