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As Evidence Grows for Role of microRNAs in Disease, Drugmakers Focus on Select Targets


By Doug Macron

As the literature describing associations between microRNAs and disease states continues to grow, so too does the number of potential therapeutic targets for molecules that either inhibit or mimic the small, non-coding RNAs.

In just the first two weeks of December, for example, at least seven papers have been published linking specific miRNAs or miRNA clusters to conditions including synovial sarcoma, pancreatic cancer, prostate cancer, and obesity.

Still, in most cases the data are early-stage, and thus far only a handful of miRNAs have made it into the pipelines of companies in the field. And to date, only one miRNA-targeting drug, Santaris Pharma's phase II hepatitis C therapy miravirsen, which targets miR-122, has been tested in humans.

Below is an overview of primary miRNA targets for which drugs are currently under development.


Given the amount of research on miR-122, as well as its abundance in the liver — an organ easily targeted by oligonucleotides — this miRNA has become a key focus for four companies: Santaris, Regulus Therapeutics, Mirrx Therapeutics, and Rosetta Genomics.

Research on the miRNA began appearing in 2005, when Peter Sarnow and colleagues at Stanford University published data showing that miR-122 is involved in HCV replication and therefore may "present a target for anti-viral intervention."

These findings have been followed by a 2008 paper from a team at Drexel University College of Medicine showing that the miRNA "greatly enhances HCV replication in non-hepatic cells" although it is "not absolutely required;" additional elucidation of miR-122's function from Sarnow's group; and an indication that "miR-122 may contribute to HCV liver tropism at the level of translation," according to researchers at Justus Liebig University.

Meanwhile, in 2006, a team from Isis Pharmaceuticals published a paper demonstrating a regulatory role for the miRNA in lipid metabolism, and dysregulation of the miRNA has been linked to liver cancer in multiple papers.

But it was in 2005 that signs were first seen that it might be possible to inhibit the miRNA therapeutically when Rockefeller University investigator and Alnylam Pharmaceuticals advisor Markus Stoffel reported that so-called antagomirs, essentially chemically modified single-stranded RNA analogs, could be used to target specific miRNAs (GSN 11/4/2005).

Among the miRNAs Stoffel and his colleagues down-regulated were miR-122.

In 2008, investigators from Santaris reported that locked nucleic acids could inhibit the miRNA in mice with no hepatotoxicity, laying the groundwork for miravirsen. That same year, the Santaris team showed that LNAs could safely inhibit miR-122 in non-human primates when delivered systemically.

Santaris followed this paper with another in late 2009 showing that miravirsen could improve HCV in non-human primates when delivered systemically (GSN 12/3/2009). These findings were released about a year and a half after Santaris had moved the drug into phase I testing (GSN 5/29/2008).

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But Santaris isn't alone in seeing commercial potential for a miR-122-targeting drug. Regulus Therapeutics, a joint venture between Alnylam and Isis, has set its sights on its own HCV drug based on the miRNA.

Taking advantage of its rights to Stoffel's antagomir technology and intellectual property generated from Sarnow's lab, both of which have been licensed by Alnylam, Regulus aims to file an investigational new drug application on an HCV drug against miR-122 in 2011 in collaboration with GlaxoSmithKline, which partnered with Regulus on the program early this year (GSN 2/25/2010).

Notably, GlaxoSmithKline had previously held an option to Santaris' miravirsen but let it expire shortly before it inked its deal with Regulus, raising questions about whether Santaris has the IP necessary to bring its drug to market. For its part, Santaris has maintained that it does.

Also setting its sights on miR-122 for HCV is Danish startup Mirrx, formerly Stealth Biotech. The company plans to inhibit the miRNA using a proprietary technology called Blockmirs, which it says can prevent individual miRNA/mRNA interactions.

The compounds are steric antisense oligos that bind to specific miRNA binding sites in target RNAs to thereby prevent the small, non-coding RNAs from binding to the same site, according to Mirrx.

"Blockmirs do not recruit any cellular enzymes which mediate degradation of target mRNAs … [so if they do] bind to a non-intended RNA, it will only cause an effect if it prevents binding of a [miRNA] or another cellular factor," an unlikely event, reducing the possibility of off-target effects, it adds.

Mirrx's efforts, however, have hit a roadblock in the form of a lawsuit filed by Santaris, which alleges that it owns the Blockmir technology (GSN 5/6/2010). Mirrx contends that the litigation is an attempt by Santaris to gain control of the technology because it is prevented from fully advancing its own LNA technology for HCV by Regulus-controlled IP.

The last company to have initiated a program against miR-122 is Rosetta, which in its early days had been pursuing therapeutics, but has since turned its focus almost entirely onto its diagnostic efforts.

It had been working on drugs targeting the miRNA for liver cancer in collaboration with Isis, but that partnership was transferred to Regulus when Isis and Alnylam established the JV. In January this year, Rosetta revealed in a US Securities and Exchange Commission filing that the companies had not renewed their alliance. Rosetta President and CEO Kenneth Berlin said a few months later that the company was still considering how to move forward with the program (GSN 3/18/2010).


In addition to miR-122, Regulus Therapeutics and partner Sanofi-Aventis are advancing a program in fibrosis that uses antagomirs to inhibit miR-21.

Although the miRNA has been implicated in various cancers by a number of different groups, it has also been shown to impact fibroblasts.

For instance, in 2008, a team from the University of Wuerzburg published data showing that miR-21, which "regulates the ERK-MAP kinase signaling pathway in cardiac fibroblasts" is up-regulated in cardiac fibroblasts in the failing heart, "augmenting ERK-MAP kinase activity through inhibition of sprouty homologue 1.

"This mechanism regulates fibroblast survival and growth factor secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy," the team wrote.

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The next year, researchers from Ohio State University reported a link between miR-21 and heart attack based on the miRNA's effect on fibroblast metalloprotease-2. And earlier this year, investigators from the University of Alabama at Birmingham published data linking the miRNA to fibrotic lung diseases.


The first significant research on miR-34 was published in 2007 by a team from Cold Spring Harbor Laboratory, which reported that the miRNA is a component of the p53 tumor-suppressor network and "may act in concert with other effectors to inhibit inappropriate cell proliferation."

The next year, investigators from Johns Hopkins University School of Medicine reported data showing that the miRNA acts as a tumor suppressor, in part through its involvement in a SIRT1-p53 pathway.

Also in 2008, University of Ulm researchers showed miR-34a to play a role in resistance to chronic lymphocytic leukemia, while in 2009 Yale University's Frank Slack and colleagues demonstrated that miR-34 is required for the DNA damage response to radiation in breast cancer cells.

Based on these and other data, Mirna Therapeutics is developing a miR-34 mimic for cancer that it hopes to move to an IND filing in 2011 (GSN 6/18/2009). Previously, the company reported preclinical data showing that the agent could inhibit tumor growth in a mouse model of lung cancer.


In 2008, Eric Olson and colleagues from the University of Texas Southwestern Medical Center first reported a link between miR-208 and heart disease when they discovered that the miRNA is "required for cardiomyocyte hypertrophy, fibrosis, and expression of beta-myosin heavy chain in response to stress and hypothyroidism."

The next year, a group from the University of North Carolina, Chapel Hill, showed that miR-208a regulates cardiac hypertrophy and conduction in mice, and that its expression was enough to trigger arrhythmias.

Having licensed IP related to the discoveries made by Olson, Miragen Therapeutics is weighing filing an IND for a miR-208-targeting drug for chronic heart failure next year (GSN 7/15/2010).

Have topics you'd like to see covered in Gene Silencing News? Contact the editor
at dmacron [at] genomeweb [.] com.

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