MicroRNAs won the Nobel — will they ever be useful as medicines?

Nobel prize: check. Medical revolution: still pending.
It took 30 years for a Nobel prize committee to recognize the discovery of tiny RNA molecules that regulate gene activity in our cells. Turning those beguiling ‘microRNAs’ into medicines, however, will take even longer.
On 7 October, this year’s Nobel Prize in Physiology or Medicine was awarded to two scientists who found and characterized microRNAs for the first time in the roundworm Caenorhabditis elegans. Since that discovery in 1993, researchers have unearthed hundreds of microRNAs in the human genome — some with tantalizing potential applications, such as treating cancer or preventing heart disease.
But so far, no microRNA-based drugs have been approved by the US Food and Drug Administration, an agency that many countries look to for guidance. The field has hit “a little bit of a slump”, says Frank Slack, who studies microRNAs at Beth Israel Deaconess Medical Center in Boston, Massachusetts.
That could be about to change: “The promise is there. The technology is getting better,” Slack says. “And the attention from the Nobel prize is really good — this will drive interest again.”
Treating disease was not on Slack’s mind when he first encountered microRNAs as a postdoctoral fellow in the 1990s. Then, he was working in Garry Ruvkun’s laboratory at Massachusetts General Hospital in Boston, where he, Ruvkun and others co-discovered the second-known microRNA, a molecule called let-7, also in roundworms1. Ruvkun shared this year’s medicine Nobel with Victor Ambros at the University of Massachusetts Chan Medical School in Worcester.

Medicine Nobel awarded for gene-regulating ‘microRNAs’

In the 1990s, researchers were interested in microRNAs because they represented a new way of regulating gene activity, Slack says. But ambitions expanded when he and his colleagues realized that let-7 was also a part of the human genome2, and might help to prevent cancer3. “We really started to think that this might have a medical application,” says Slack. “The first clinical trial came very quickly after that.”
Maybe a little too quickly, he adds.
That first trial investigated a microRNA similar to let-7, called miR-34, that also held the potential to stave off cancer. Studies in mice with lung cancer showed that administering a molecule similar to miR-34 early in the disease could slow tumour growth4. But at the time, researchers knew little about how to cloak RNA medicines to keep them from provoking a dangerous immune response, or how best to deliver them to the right spot in the human body.
As a result, says Slack, clinicians had to administer unusually high doses of the experimental drug into the bloodstream of trial participants. This triggered an immune response, and four people died. The trial was stopped.
Since those early days, researchers in academia and industry have learned how to package or modify RNA molecules so that they can be delivered to certain organs safely and at lower doses, says Anastasia Khvorova, a chemical biologist at the University of Massachusetts Chan Medical School.

Scientists are waiting longer than ever to receive a Nobel

But the miR-34 trial wasn’t the only disappointment along microRNA’s path to becoming a medicine. Another came when researchers at the San Diego, California, site of Santaris Pharma tested a therapy designed to reduce the expression of a human microRNA that is commandeered by the hepatitis C virus to infect liver cells. Early results in people with chronic hepatitis C virus infections seemed positive5. “It was a milestone,” says Sakari Kauppinen, who studies RNA-based medicine at Aalborg University’s campus in Copenhagen, and worked on the team at Santaris.
But as the researchers were celebrating, another company announced that it had developed a more conventional treatment for hepatitis C. Fearing that it could not compete, Santaris abandoned the microRNA approach, Slack says.
Despite those false starts, there is every reason to expect that microRNA-based medicines will have their day, Khvorova says.
Researchers are developing microRNA-based therapies to treat epilepsy, obesity and cancer. In March, in a sign of confidence in microRNAs, the pharmaceutical firm Novo Nordisk in Bagsvaerd, Denmark, agreed to pay up to €1.025 billion (US$1.12 billion) to purchase a company called Cardior Pharmaceuticals in Hannover, Germany. Cardior is conducting a phase II clinical trial of a microRNA inhibitor designed to treat heart failure.
Another reason to expect success for microRNAs is that other drugs based on RNA have been approved and work through very similar mechanisms, Khvorova says. Those drugs, several of which are designed to treat genetic disorders such as hereditary high cholesterol, rely on a technique called RNA interference to reduce the activity of a target gene. One difference between them and microRNAs, however, is that microRNAs are made naturally by the body and often affect the activity of many genes, Khvorova adds. This means that careful laboratory studies will be necessary to ensure that boosting or suppressing a natural microRNA won’t have unwanted side effects.

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Over the years, those microRNA data have been accumulating, says Khvorova, and the field might be nearing a tipping point. “It’s lagging behind, but it’s coming,” she says. “I am confident that there are several programmes that are likely to generate drugs.”
In the meantime, Slack, who has advised and founded several companies involved in developing microRNA therapies, has returned years later to miR-34. Armed with better methods for delivering the treatment in the body, he’s hopeful that the microRNA’s ability to simultaneously affect multiple genes that have a role in protecting against tumours could help to treat particularly recalcitrant cancers, such as pancreatic cancer.
“I never gave up on it,” he says.