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As microRNA Field Heats Up, Biotech Begins to Embrace the Technology. Will Pharma Follow?

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For years, the importance of microRNAs has been almost entirely appreciated by academic researchers. But in recent months, as evidence accumulates linking these small non-coding RNAs to both normal biological functioning and disease accumulates, the biotech industry • known for pioneering new technologies • has started to take notice.

But what of big pharma? In light of that industry's slow acceptance of RNAi as a therapeutic modality even with promising clinical data available, it is likely to be some time before it truly embraces miRNAs.

Since the first miRNA, lin-4, was discovered more than a decade ago, hundreds more have been identified in mammals, invertebrates, and plants, and research about the roles these RNAs play has been piling up.

In late 2004, Rockefeller University researchers published data in Nature showing that the evolutionarily conserved and islet-specific microRNA miR-375 regulates insulin secretion. Two months later, Whitehead Institute researcher David Bartel published data in Cell suggesting that miRNAs may be responsible for regulating up to one-third of all human genes (see RNAi News, 1/21/2005).

Early last year, a team from Yale demonstrated that one highly studied miRNA, let-7, may act as a tumor suppressor through its inhibition of the human oncogene RAS (see RNAi News, 3/11/2005). A few months later, a group from the University of California, San Francisco, published data showing how the simian virus 40 uses miRNAs to improve its chances of successful infection (see RNAi News, 6/10/2005).

More recently, researchers from two Massachusetts Institute of Technology labs published data indicating that up to a third of the human genome may be regulated by microRNAs (see RNAi News, 12/2/2005). A few months later, a team composed of researchers from academia and industry reported that the human genome contains significantly more miRNAs than have been currently identified after finding more than a hundred novel miRNA candidates in human colorectal cancer cells (see RNAi News, 3/2/2006).

Last November, amid these and other findings, Alnylam formally threw its hat into the miRNA ring when it took an exclusive license to antagomirs • a new class of oligos designed to selectively inhibit miRNAs in vivo (see RNAi News, 11/4/2005).

Developed by Markus Stoffel, a Rockefeller University researcher and member of Alnylam's scientific advisory board, antagomirs are chemically modified single-stranded RNA analogues complementary to a specific miRNA. To improve cellular uptake and target degradation, the oligos are also linked to a cholesterol molecule.

As it focuses on its RNAi drug efforts, Alnylam has not said much about the status of its miRNA-targeting drug programs. Neither has its top rival Sirna Therapeutics, which followed Alnylam's lead less than two months ago when it licensed from the University of Massachusetts Medical School the exclusive rights to a series of patents covering a novel miRNA-modulating technology called anti-RISC (see RNAi News, 5/11/12006).

One company that has been forthcoming with its plans for its miRNA programs is Israel's Rosetta Genomics, an miRNA diagnostics and therapeutics developer.

In November, Rosetta Chairman and CEO Isaac Bentwich told RNAi News that his company was planning a US initial public stock offering in 2007 • a move that would be made after the company formed a handful of collaborations to develop miRNA diagnostics and/or therapeutics (see RNAi News, 11/4/2005).

Rosetta has already signed at least one partnership agreement, with Ambion spin-out Asuragen; the companies are working together to develop three new diagnostic products for prostate cancer.

In February, Rosetta also signed a deal with Isis Pharmaceuticals to discover and develop antisense drugs that regulate miRNAs as a treatment for liver cancer (see RNAi News, 2/23/2006).

Isis, which has been exploring the RNAi and miRNA fields after antisense failed to live up to live up to its earlier hype, has published data showing that a 2'-O-methoxyethyl phosphorothioate antisense oligonucleotide could be used to inhibit the expression of the liver-specific miRNA miR-122. The company also presented data at the American Diabetes Association's 66th Annual Scientific Sessions in Washington, DC, last month showing that inhibition of miR-122 improved the health of obese mice without significant side effects (see RNAi News, 6/15/2006).

Rosetta President Amir Avniel recently noted that his company views "antisense as the optimal platform for inhibiting miRNA function."

Santaris Pharma, which is developing locked nucleic acids as miRNA-targeting drugs, may disagree.

LNAs are a class of nucleic acid analogs in which the ribose ring is locked by a methylene bridge connecting the 2'-O atom with the 4'-O atom • features designed to increase affinity and stability.

In May, Sakari Kauppinen, associate director of miRNA research at Santaris, told RNAi News that his company has achieved significant drops in plasma cholesterol levels in mice using intravenously delivered LNAs targeting miR-122 (see RNAi News, 5/4/2006). Based on these and other data, Santaris expects that it could have an miRNA drug in clinical trials by late 2007.

But the pharmaceutical industry is traditionally a cautious one, always hedging its bets. To date, only a handful of big pharmas have ventured out to collaborate with RNAi drug makers. Among those is GlaxoSmithKline, for example, which recently signed a multi-year alliance with Sirna to discover, develop, and commercialize RNAi-based drugs for respiratory diseases such as asthma (see RNAi News, 4/6/2006).

Though the deal would seem a validation of Sirna and RNAi in general, GlaxoSmithKline's apparent commitment should be taken with a grain of salt. At the Cambridge Healthtech Institute's Beyond Genome conference last month, Pearl Huang, vice president of biology, oncology, and proliferative diseases at GlaxoSmithKline, noted that RNAi is one post-genomic technology her company is not entirely convinced about.

She added that it is still early days for the technology, which remains untested in large-scale clinical studies and could ultimately prove to be toxic as a therapeutic • a sentiment suggesting that big pharma, even when it has begun to get its toes wet, doesn't jump right in.

• Doug Macron ([email protected])

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