Targeting a Master Regulator of Disease

Drugmakers place big bets on the emerging science of microRNA.

San Diego startup Regulus, founded in 2007, has quietly been working on a new way to target RNA for drug development. The company has been studying a subset of RNA molecules called microRNAs, or miRNAs. First discovered in the 1990s, misbehaving miRNAs have been linked to several diseases, including cancer and heart failure. Drug developers hope these molecules will prove to be particularly effective drug targets because manipulating just one seems to suppress several disease-linked proteins--whereas most biotech drugs only target individual proteins.

Healing the heart: Inhibiting microRNAs reduces the buildup of dangerous collagen (shown in red) typical of cardiac fibrosis, an abnormal thickening of the heart valves that can lead to heart failure. The bottom image shows cells that have been treated with an anti-microRNA agent. Credit: Regulus Therapeutics

Regulus is co-owned by Alnylam and Isis, leaders in RNA-based drug development. While it is just one of a handful of startups developing miRNA therapeutics, it has attracted significant attention from big pharmaceutical companies. Last month, French pharmaceutical giant Sanofi-Aventis announced a research alliance with the company. Sanofi has pledged up to $750 million in payments, including $35 million up front to Regulus--an unusually large investment in such early-stage science. Sanofi and Regulus will work together to target fibrosis, an excessive buildup of hard collagen that can wreak havoc on the heart, kidneys, and other organs. Regulus already has a multimillion-dollar alliance with GlaxoSmithKline to codevelop drugs to treat immune diseases and a hepatitis C treatment.

While many RNAs encode proteins, miRNAs instead regulate the expression of multiple genes by preventing protein-coding RNAs from fulfilling their function. That, in turn, controls everything from metabolism to immune response to muscle development. About 700 miRNAs have been identified so far.

"The analogy we like to use is that miRNA is the maestro conducting the orchestra--the entire biological network," says Zak Zimmerman, Regulus's director of business development. "If something goes wrong with the maestro, the orchestra starts to play off-key."

Regulus has synthesized several compounds that block or modify "oligonucleotides"--the chains of nucleotides that comprise miRNAs. In 2008, the company demonstrated that it could inhibit a particular miRNA in mouse hearts, reversing a fibrotic condition that causes heart failure. Regulus is also researching potential remedies for renal fibrosis, a major cause of kidney failure and common complication among transplant patients. Sanofi had a team of scientists researching miRNA for quite some time, but they lacked the chemistry know-how to transform their discoveries into drugs.

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Despite their promise, translating miRNA targeting compounds into safe drugs is likely to prove challenging. MiRNAs control many bodily processes, so altering them can cause unwanted side effects. "They're promiscuous--they affect multiple downstream components," says Sumit Chanda, associate professor at the Sandford Burnham Medical Research Institute in La Jolla, CA. "The more targets you take out, the more toxicities there can be."

Regulus's scientists acknowledge that they'll have to perform extensive toxicity testing before they identify molecules that are safe for testing in people. Funding from Sanofi and GSK will help move that testing forward. The company expects to choose its first drug candidate for clinical trials by the end of this year.