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The Miracle of microRNA

San Diego researchers are delving into the mysteries of microRNA and its potential cures for a host of major diseases. Breakthrough results - and a Nobel Prize - appear to be right around the corner.


In 1993, Dartmouth researcher Dr. Victor Ambrose noticed something peculiar deep within the genes of tiny, 1-millimeter-long worms called C. elegans: An extremely small ribonucleic acid (RNA) molecule, located in a segment of the genome previously thought to have little function, appeared to regulate the growth of a specific protein abundance. The significance of his discovery, noted in scientific journals, wasn’t fully understood until 2000 when scientists detected a second, separate RNA molecule that controlled another specific gene function — and demonstrated that these molecules are present in other life forms, including human beings. They were dubbed microRNA (also called miRNA and miR), and the hunt was on to find more and determine what functions they regulate — and how to manipulate them to potentially manage and eradicate deadly diseases including cancer, immune-system issues and heart disease.

San Diego is poised to be a hub of micro­RNA innovation, with groundbreaking tumor research at UCSD and mass-market endeavors at Regulus Therapeutics. The payoff potential is immense — as is the opportunity to win a Nobel Prize.

Controlling Cancer by Starving Tumors

Over the past 20 years, UCSD biologist Dr. David Cheresh has actively sought to control the power switch that turns ordinary blood vessels into the fuel pipes that feed out-of-control tumors. “Tumors grow as long as they have nutrients, and therefore the blood-vessel supplies have to grow as fast as the tumor,” Cheresh says. This rapid expansion of blood-vessel networks, called angiogenesis, has been the focus of scientists looking at alternatives to directly attacking tumors for treating cancer. “If we can figure out how to turn [blood vessel growth] off, we can starve tumors,” Cheresh says.

Cheresh and his research lab at UCSD’s Moores Cancer Center in La Jolla theorized that microRNA —a switch mechanism in itself — might have the capability to control the growth. “MicroRNA turns off genes, so we set out to find the one that, when turned off, allowed blood vessels to grow like crazy, like an emergency brake that gets released,” he says. Starting two years ago with human blood vessels created from stem cells in culture dishes for his research, Cheresh found that miR-132, a specific microRNA molecule, was present in the vessels leading to cancerous tumors but not in vessels leading to nontumorous tissues. This appeared to be a key.

“The tumors had figured out a clever trick: They turned on the miRNA and created a growth process that had no way of being stopped,” says Cheresh.

Further research showed that a microRNA molecule could be deactivated with the introduction of a complementary anti-microRNA. “It’s easy to devise the anti-miRNA once you know the microRNA, and it reapplies the brake,” says Cheresh. “The tumor doesn’t like this and starts to shrink and wither away. The exciting thing is that the miRNA we’re targeting is only in those specific blood vessels. It doesn’t impact the other cells.”

Their tests worked beautifully on tumorous mice. The next step was to determine how to deliver the anti-miR molecule to the tumor. Direct injection proved effective for easily accessed tumors, but for harder-to-reach internal locations, they needed a way to get the molecule to the tumor and stay put.

Cheresh and his lab set out to create a nanoparticle designed to target and choke the blood vessels leading to tumors. “The nanoparticle is like a smart bomb, a guided missile,” he explains. “It’s extremely small — billions can be sent in. We’re at the level of molecular targeting, which minimizes collateral damage.” The nanoparticle is injected into the bloodstream, where it quickly circulates through the body until coming into contact with cancerous vasculature. Then it locks on and delivers its anti-miR payload to begin the shutdown process.

The implications are staggering: Cancer may have finally met its match. But the angiogenic developments Cheresh and the study’s first author, Sudarshan Anand, are pioneering don’t stop there. Angiogenesis is a key component of diseases including macular degeneration, psoriasis and inflammatory illnesses, and initial tests show promise that anti-miR will help control them as well.
Beyond that, Cheresh notes, the miR-132 function in stimulating vascular growth has the potential to be harnessed to drive blood and nutrients to damaged or blocked areas. Heart disease and heart-attack victims would benefit from such treatments. Although his lab hasn’t tested this directly, Cheresh says it’s easy to imagine using the molecule for such means.

Turning microRNA Findings into drugs

A few blocks north of Cheresh’s lab, Regulus Therapeutics is also establishing itself as a leader of microRNA research and innovation. Born in 2007 through a partnership between Carlsbad‘s Isis Pharmaceuticals and Boston’s Alnylam Pharmaceuticals, the laboratory has set out to identify, create and take to market a set of groundbreaking drugs that target yet-to-be-cured diseases.

Working with two pharmaceutical giants, it may be the first company to do so. In April 2008, GlaxoSmithKline and Regulus Therapeutics announced the first micro­RNA-focused strategic alliance to discover, develop and commercialize novel microRNA-targeted therapeutics to treat inflammatory diseases such as rheumatoid arthritis. With a potential value of $600 million, the deal was huge for a company as young as Regulus, which entered the partnership just six months after forming.

Further demonstrating confidence in Regulus as a leader in the microRNA field, GlaxoSmithKline launched a second endeavor with the company in February 2010 to develop and commercialize microRNA therapeutics targeting hepatitis C, focusing on exclusive patent rights Regulus has for manipulating miR-122 for treatment. Most recently, multinational pharmaceutical giant Sanofi-Aventis awarded Regulus with the largest microRNA partnership to date — targeting fibrosis — with a potential value of $750 million for the research lab.

With millions invested in its microRNA research, the biggest challenge for Regulus is to limit itself. “The hardest part for us is what not to focus on first,” says CEO and president Kleanthis Xanthopoulos. Indeed, with the prospect of curing a wide range of major diseases, maintaining a structured and disciplined approach is a major test for a company that still employs fewer than 50.

But Regulus is maintaining that size purposefully, says Xanthopoulos. “Most of our employees right now are in R&D, and we want to stay small. We are highly reactive and interactive — our size is a cultural and strategic objective. Over the next four years we’ll slowly move to clinical testing, and by year five we should be selling products.”

Though it remains small internally, Regulus does collaborate with many external laboratories — a primary reason its offices are in Torrey Pines, close to UCSD, Scripps, Salk and other medical tech offices. Its active network of more than 50 academic micro­RNA researchers, including neighbor David Cheresh, is expanding.

“The next step in research is to find if we can overcome the problems in making these into drugs,” Cheresh says. His lab plans to meet with Regulus to solve the problem of the anti-miR132 molecule getting caught and flushed by the liver — the primary obstacle to allowing this treatment to be turned into an effective and affordable medicine.

Dr. Hubert Chen, Regulus’ vice president of translational medicine, guides discoveries like Cheresh’s into potential medications, one of the biggest hurdles for any new technology. Two milestones need to be met, he explains, before a microRNA medication is on the market. First, the ability to develop medicines to treat disregulated microRNAs in humans has to be demonstrated. The field of microRNA is so novel that human testing has barely begun. Chene predicts this will happen in the next few years. After that, FDA approval will need to be granted, which means clinical trials that can take an additional few years.

Regulus’ scientific advisory board chair, David Baltimore, a 1975 Nobel emeritus, maintains a realistic outlook on the company’s challenges and a sense of the frontier they are entering: “The key is to be able to direct therapeutic RNAs to specific cells in the body. Widening this ability to many new cell types is a key need for Regulus, and one that is actively being pursued. Once this is solved, many new opportunities will open up, and the sky will be the limit.”   

A Nobel Experiment?

Though only a recent innovation, the field of microRNA has already garnered re­spectable awards, including a 2008 Lasker Award, generally considered the precursor to winning the Nobel Prize. But despite all the attention a Nobel would generate, the scientists are focusing on the human rewards of the tech­nology.

“I’m having too much fun doing the science and making new discoveries to worry about prizes,” says Dr. David Cheresh. “I would prefer to consider how our discoveries will make a difference in the lives of cancer patients. We have discovered drugs that have already made an impact on cancer. Nothing could be more rewarding than that.”

Regulus’ head of chemistry, Dr. Balkrishen Bhat, echoes that. “The fascination, the pursuit, is enough for me. If I made a difference in a few patients in my lifetime, that would be the reward.”

Cheresh understands that he is opening the doors to a new age of medicine. “It is very exciting to approach the forefront of a field and begin to understand what Mother Nature had in mind when she designed some of the molecular pathways that regulate cells and tissues,” he says. “Once we understand these pathways, [we] understand the molecular basis of disease, [and we can] begin to develop new therapeutic strategies. Putting all of this together is a lifelong process that is very satisfying and invigorating. It keeps my adrenaline pumping.”

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