Hepatitis C-Small RNAs and the Clinic

Small RNAs and the Clinic
February 2011
By Matthew Dublin

Each month, more and more evidence emerges to link microRNAs to a range of diseases. Despite all their progress in making miRNA-gene expression connections, researchers on the front lines of RNA research say they have only recently begun to understand how these tiny molecules — typically one one-thousandth the size of an mRNA molecule — actually function.
"The basic biology of microRNAs is still poorly developed, and although we have really seen an explosion in the study of microRNAs in the last two or three years, it takes longer than that to really have a good grasp of what the general functions of them are — and even longer to figure out the specific functions. So I think it's very early in the field," says MIT's Phillip Sharp, who was the co-recipient of the 1993 Nobel Prize in physiology or medicine. "Clearly, you can deliver single-strand nucleic acids or inhibitors of single-strand nucleic acids [to] cells in a clinical setting. I think there are open avenues and it will just take awhile to work it all out."
Moving miRNAs into the clinic has gained momentum since 2005, when researchers at Rockefeller University used modified single-stranded RNA analogs, or antagomirs, to target specific miRNAs. During the last few years, a small but growing number of miRNAs have been incorporated into pharmaceutical companies' drug-development pipelines. Some miRNA researchers say they envision diagnostic roles for these molecules more than therapeutic ones. Late last year, Rosetta Genomics, which has brought three miRNA tests to the market, announced an improved version of its miRview Mets diagnostic tool, which the company says can identify 42 tumor types of unknown origin.
There are currently a handful of miRNAs in the sights of several pharmaceutical companies. One miRNA target that is ripe for clinical development is miR-21, which is thought to be up-regulated in cardiac and lung fibroblasts as well as in several different types of cancers. Regulus Therapeutics and Sanofi-Aventis have partnered up to establish methods for inhibiting miR-21 with antagomirs. With support from several studies demonstrating that miR-34 played a key role in the p53 tumor-suppressor network, Mirna Therapeutics began a program last year to develop a -miR-34 mimic that could be used to treat various cancers. Miragen Therapeutics has licensed the 2008 work of the University of Texas Southwestern Medical Center's Eric Olson — in which he linked miR-208 to heart disease — with the hopes of developing an miRNA-targeting drug for heart failure.
But the miRNA that has attracted the most attention for the clinic is miR-122. Rosetta Genomics, Santaris, Regulus Therapeutics, and Mirrx Therapeutics are all interested in this particular miRNA, which has been shown to play a role in replication of the hepatitis C virus. The only miR-122-targeting drug that has been tested in humans to date is Santaris Pharma's phase II hepatitis C therapy, miravirsen. It might not be the only one for long, though, as Regulus Therapeutics and GlaxoSmithKline teamed up last year to develop their own hepatitis C drug candidate that targets miR-122.
In the liver
As miR-122 has been shown to be expressed highly in the liver, diseases that affect this organ are attractive — and potentially the most tractable — prospects for miRNA-based therapeutics.
To date, researchers have added more than 5,000 microRNAs to a stockpile of data that promises to shed light on the range of roles these endogenous molecules play in various diseases, and propogates their potential as tools for the clinic
http://www.genomeweb.com/small-rnas-and-clinic?page=2