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Biotech / Medical : RNAi -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (563)	3/29/2008 12:15:11 PM
From: idos	Respond to of 671

Tuck, miRNAs are single-stranded not dsRNA, so they should not have that problem of stimulation of the innate immunity pathway by dsRNAs. Moreover, companies like Asuragen or ROSG, developing microRNA-based diagnostics and not drugs, will not have this problem anyway. Found in rnainews.com comments from some figures in the field: "Anyone who is practiced in the art is not surprised that toll-like receptors are involved in nucleic acid recognition and downstream signaling leading to interferon production, et cetera," Alan Sachs, vice president of RNA therapeutics at Merck Research Laboratories, told RNAi News this week. "In many ways, [the paper] confirms what we [at Merck] believe: that heavily chemically modified RNA is going to be a differentiation that will be needed to play in the marketplace." Another researcher, City of Hope's John Rossi, said that In addition to "smart use" of chemical modifications, the use of delivery vehicles for siRNA drugs will likely be key to overcoming the kind of effect described in the Nature paper. Neither Sachs or Rossi participated in the study. However, Rossi reviewed the paper for Nature prior to its publication. Jayakrishna Ambati, a University of Kentucky professor and senior author of the Nature paper, agreed. "If one wants to realize the real sequence-specific, gene-silencing potential of these molecules, [the activation of toll-like receptors] has to be taken into account and somehow perturbed either through siRNA modification or some other mechanism," he told RNAi News. Overall, the paper "doesn't detract from how powerful RNAi is," Rossi noted. "It just tells people that when you are doing these experiments, you've got to consider the innate immune response as something that is very critical for the interpretation of your data and results. "We go marching along thinking that [the drugs in] all of these clinical trials that are taking place are working by the mechanism that you think they are," he added. "Here's a clear case where they're not, at least in the mouse model that they used." It is, in fact, that mouse model that Opko's Reich argued may be the source of what he believes are inaccuracies in the data. Calling the laser injury-induced CNV model "technically difficult," Reich said that "everyone who works with this model knows that you must take the results with great caution. It is a first model that is tested and followed up by many other models to look for confirmation." But Ambati and his colleagues did not provide any such confirmation, he noted. To fully understand the data in the Nature paper requires "confirmation of this model by other independent labs because it is very common for different labs to get different findings … using the laser-induced mouse model of CNV." Opko's data showing the RNAi-mediated silencing of VEGF, meantime, has been validated by the company in multiple models, as well as by independent labs, Reich said. "We are resting on a comprehensive body of data that goes well beyond the laser-induced model to show the safety and efficacy and VEGF silencing of bevasiranib including an entire [pharmacology and safety data] package that was submitted to [the US Food and Drug Administration], as well as clinical results from three clinical trials supporting the biological effect and showing a signal indicative of efficacy," he said. "We've very confident bevasiranib mediates VEGF silencing." A representative from Allergan directed request for comment to Merck, which acquired Sirna about a year ago (see RNAi News, 1/4/2007), although a Merck spokesman told RNAi News that his company could not comment directly on AGN211745 since it had been licensed to another company.<< My own first reaction to the Kleinman et. al. paper was - wow! their control worked too well...