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Advances in microRNA Field Help Define 2009 While RNAi Advances Despite Setbacks

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By Doug Macron

Although the RNAi field reached a variety of milestones during 2009, notably the initiation of new clinical trials, advances made with microRNAs topped the list of key events for a number of industry players.

"I've been absolutely blown away by the microRNA field and the way it's blossomed," University of Massachusetts Medical School researcher and Nobel laureate Craig Mello told RNAi News this month. "There is just one story after another [showing that] microRNAs … are very critical to many aspects of either disease or development."

John Rossi, an investigator at the City of Hope, agreed. "I think it was the year of the microRNA this time around," he said.

In line with the growing trend of "studying microRNA function … [and] the roles of individual microRNAs in disease … there have been a number of really nice papers [showing] that up- or down-regulation of a single microRNA … leads to various states of health or disease," he noted. "It's becoming increasingly clear that even a single microRNA … can have a profound impact" on biology.

To UMMS professor and miRNA pioneer Victor Ambros, a notable development in the miRNA field for the past year was the publication of a paper in Nature by Rockefeller University's Robert Darnell detailing a new method, dubbed HITS-CLIP, for identifying targets of the small, non-coding RNAs.

"Recently, high-throughput sequencing of RNAs isolated by cross-linking immunoprecipitation has identified functional protein-RNA interaction sites," according to the paper. In their work, Darnell and colleagues used the approach to "covalently crosslink native argonaute protein-RNA complexes in mouse brain."

They "produced two simultaneous data sets — Ago-miRNA and Ago-mRNA-binding sites — that were combined with bioinformatic analysis to identify interaction sites between miRNA and target mRNA," they wrote in the paper.

"This allows, for the first time, a direct characterization of the mRNA sequences protected by argonaute and, therefore, engaged with a microRNA in vivo," Ambros said. "It's a very powerful technique that allows us to go beyond simply computational prediction of microRNA targets. That's a significant advance and it's going to shape what a lot of people are doing."

But perhaps of greater interest were data published this month in Science by investigators at Santaris Pharma, who showed how a locked nucleic acid could be used to inhibit miR-122, which is essential for hepatitis C virus replication, in non-human primates with no side effects and improve HCV-induced liver pathology (see RNAi News, 12/3/2009).

"I think the Santaris [paper] is the technological highlight of the year," UMMS researcher and Alnylam Pharmaceuticals co-founder Phillip Zamore told RNAi News. "The idea that you can inhibit microRNA function and suppress HCV infection in a chimp — that to me is just incredible."

The work by Santaris, which completed a phase I study of a miR-122-targeting LNA drug this year (see RNAi News, 5/7/2009), "is an important proof of principle that we can treat microRNAs as a target for drug therapy," Rossi said. "That's huge."

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Despite the progress, "it's still early days" for miRNA-targeting therapeutics, he cautioned. Currently, people are using "very chemically modified … oligos. Looking at off-target effects and toxicity are going to be big issues that, in my mind, haven't been explored in enough detail."

'Where are the Breakthroughs?'

When it comes to work done in the RNAi space during 2009, "I don't think there have been so many bright spots," Johannes Fruehauf, vice president of medical affairs at Cequent Pharmaceuticals, told RNAi News this month. "The field started 10 years ago, and the first clinical trial [of an RNAi drug] was in 2004. We've been waiting for some better results than the ones that came out this year."

"Where are the breakthroughs and clinical results that are eye-popping and make people say, 'Wow, this field is really coming along?'" Cequent President and CEO Peter Parker added.

Indeed, 2009 saw the end of development of what had been the industry's most advanced drug candidate, Opko Health's wet age-related macular degeneration treatment bevasiranib, due to poor performance in a phase III trial (see RNAi News, 3/12/2009).

And this summer, Alnylam announced that its siRNA-based treatment for respiratory syncytial virus, ALN-RSV01, met the primary endpoint of a phase II study, but indications of efficacy were less dramatic than some industry watchers had expected (see RNAi News, 7/23/2009).

But according to MDRNA President and CEO Michael French, setbacks seen during the year are merely the kind of growing pains experienced with any new technology, and while there may not have been any earth-shattering developments, "you're seeing … continued progress of the sector — new programs going into clinical development, new technologies, new data."

There has been "a continued advancement of the science, which talks to [RNAi] being mainstream and real … not just this kind of cool science project," he said. "As you look at this as a new therapeutic area, I think we're … getting it done.

"That's the highlight for the year — it's getting done," French said. "There are companies with clinical programs, there are companies with non-human primate data, there are companies getting licensing transactions done. The highlight is all these things moving forward."

Part of the effort to move things forward has been continued work on the ever-present delivery challenge, Paul Burke, executive director of RNA therapeutics at Merck, told RNAi News.

"There have been some really important technical advances in the delivery arena, and you've seen evidence of that with recent clinical entries," he said. "That to me is a pretty significant development because delivery is acknowledged as being the key challenge that needs to be overcome to realize the full potential of RNAi."

In 2009 alone, at least three RNAi drugs entered phase I testing, including Tekmira Pharmaceuticals' hypercholesterolemia drug ApoB SNALP (see RNAi News, 7/9/2009), Silence Therapeutics' cancer treatment Atu-027 (see RNAi News, 7/9/2009), and Sylentis' glaucoma-associated ocular hypertension therapy SYL040012 (see RNAi News, 8/20/2009).

"Here we are in 2009 with half a dozen clinical-stage programs," just about five years after Alnylam reported the first in vivo demonstration of RNAi gene knockdown in mammals using systemically administered siRNAs, French noted. "That's pretty amazing."

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