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MicroRNAs and the Nobel Prize: Will they ever be useful as medicines?
The Nobel Prize for microRNAs raises questions: When will these molecular discoveries be used as drugs?
MicroRNAs and the Nobel Prize: Will they ever be useful as medicines?
Nobel Prize: Checked off. Medical revolution: Still open.
It took thirty years for a Nobel Prize committee to discover tiny RNA molecules Gene activity regulate in our cells. However, converting these fascinating “microRNAs” into drugs will take even longer.
On October 7th the Nobel Prize in Physiology or Medicine was awarded awarded to two scientists who developed microRNAs discovered and characterized for the first time in the nematode Caenorhabditis elegans. Since that discovery in 1993, researchers have found hundreds of microRNAs in the human genome - some with promising applications, such as treating cancer or preventing heart disease.
But so far, no microRNA-based drugs have been approved by the U.S. Food and Drug Administration, an agency that serves as a benchmark in many countries, and the industry is currently in a "bit of a weak period," according to Frank Slack, who studies microRNA at Beth Israel Deaconess Medical Center in Boston, Massachusetts.
However, that could soon change: "The potential is there. The technology is improving," says Slack. “And the attention through the Nobel Prize is really positive – it will spark interest again.”
Growing ambitions
Treating disease wasn't a priority for Slack when he first came across microRNAs in the 1990s. At the time, he was working in Garry Ruvkun's lab at Massachusetts General Hospital in Boston, where he, Ruvkun and others discovered the second-known microRNA, called let-7, also in nematodes 1. Ruvkun shared the Nobel Prize in Medicine this year with Victor Ambros of the University of Massachusetts Chan Medical School in Worcester.
In the 1990s, researchers were interested in microRNAs because they represented a new way to regulate gene activity, Slack said. But his ambitions grew when he and his colleagues realized that let-7 was also part of the human genome 2 and could potentially help prevent cancer 3. “We really started to think that this could have medical applications,” says Slack. “The first clinical trial came very quickly after that.”
Maybe a little too fast, he says.
This first study tested a microRNA similar to let-7 called miR-34, which also had the potential to ward off cancer. Studies in mice with lung cancer showed that administering a molecule similar to miR-34 early in the disease could slow tumors 4. But at that point, researchers knew little about how to package RNA drugs to avoid a dangerous immune reaction or how best to deliver them to the right place in the human body.
As a result, clinicians had to administer unusually high doses of the microRNA into the study participants' bloodstream. This triggered an immune reaction and four people died. The study was stopped.
Disappointments everywhere
Since those early days, researchers in academia and industry have learned how to package or modify RNA molecules so that they can be delivered safely and at lower doses to specific organs, said Anastasia Khvorova, a chemical biologist at the University of Massachusetts Chan Medical School.
But the miR-34 study wasn't the only disappointment on the path to turning microRNA into a drug. Another came when researchers at Santaris Pharma in San Diego, California, tested a therapy aimed at reducing the expression of a human microRNA used by the hepatitis C virus to infect liver cells. Initial results in humans appeared to be positive 5. “It was a milestone,” says Sakari Kauppinen, who studies RNA-based medicine at Aalborg University in Copenhagen and worked on the team at Santaris.
While the researchers were celebrating, another company announced that it had developed a more conventional treatment for hepatitis C. Santaris abandoned microRNA approaches out of fear of not being able to compete, Slack said.
Despite these false starts, there is every reason to expect that microRNA-based drugs will have their moment, says Khvorova.
Researchers are developing microRNA therapies to treat epilepsy, obesity and cancer. In a sign of confidence in microRNAs, drug company Novo Nordisk in Bagsvaerd, Denmark, agreed in March to pay up to 1 billion euros ($1.1 billion) to buy a company called Cardior Pharmaceuticals in Hanover, Germany. Cardior is conducting a Phase II study of a microRNA inhibitor designed to treat heart failure.
A turning point is coming?
Another reason to expect success for microRNAs is that other RNA-based drugs have been approved and work with a very similar mechanism, says Khvorova. These medications, designed to treat conditions such as high cholesterol, are based on a technique called RNA interference, to reduce the activity of a targeted gene. However, one difference between them and microRNAs is that microRNAs are produced naturally by the body and often influence the activity of many genes, Khvorova adds. This means that careful laboratory studies are necessary to ensure that raising or lowering a natural microRNA does not cause unwanted side effects.
Over the years, this body of microRNA data has accumulated, says Khvorova, and the field may be nearing a tipping point. “It’s lagging behind, but it’s coming,” she says. “I am confident that there are several programs that are likely to produce drugs.”
Meanwhile, Slack, who has consulted for and founded several companies involved in developing microRNA therapies, returned to miR-34 years later. Equipped with better ways to deliver the treatment in the body, he hopes that microRNA's ability to simultaneously affect multiple genes involved in tumor defense could help in particularly difficult-to-treat cancers, such as pancreatic cancer.
“I never gave up,” he says.
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