In 1998, two researchers made a startling discovery with enormous potential: They could attack diseases by turning off the genes that provide them with their malevolent energy.
The scientists, from the University of Massachusetts Medical School and Stanford University, had come up with a way to block, or “silence,” genes by using strands of ribonucleic acid, or RNA, to interfere with the genes’ normal production of proteins. Remove the proteins and the diseases fed by them would go away.
But by the time Craig Mello and Andrew Z. Fire were rewarded for their breakthrough with the Nobel Prize in Medicine in 2006, their big idea, called RNA interference, or RNAi, had failed to produce big breakthroughs.
The gene manipulation that had worked so well in worms was proving trickier in people. The Great Recession hit, and many people forgot about the idea. Only a handful of companies kept at it, believing RNAi held real promise.
Then, a few years ago, researchers achieved that key breakthrough: getting tiny strands of interfering RNA past a gauntlet of defenses to pair up with their exact cousins in the gene-production line.
“There’s been significant progress made on the delivery front, which has held back the field over the past decade,” said Andre Turenne, head of strategy and business development for Genzyme Corp., which recently signed a major development deal with a fellow Cambridge biotech company, Alnylam Pharmaceuticals Inc.
For a gene to produce a protein, DNA has to send the recipe for that specific protein via a single strand of nucleic acids called messenger RNA. RNAi intercepts this messenger, cutting it up before it can deliver the recipe, so the protein is never made.
The trick was getting the RNAi in contact with the messenger RNA. The RNAi kept getting rebuffed outside of the cell, or it turned on the body’s antiviral response and got attacked by immune cells, said Phillip D. Zamore, a Howard Hughes Medical Institute investigator and codirector of the RNA Therapeutics Institute at UMass Medical School.
But researchers at Alnylam figured out a way in. They first made the RNAi strand much shorter — it’s now technically called a short-interfering RNA, or siRNA — and then disguised it inside a tiny ball of fats that can slip inside the cell unnoticed by the immune system.
Once inside, the interfering RNA lived up to its name, arresting diseases by dialing down the production of proteins.
“All of human disease is either caused by too much protein or too little protein,” said John Maraganore, Alnylam’s chief executive.
“Essentially, every single disease is too much of a bad protein or too little of a good one.”
This delivery system also allows Alnylam to readily tailor its RNAi to go after different proteins, Maraganore said.
“We’ve now got an ability to create a sustainable flow of genetic medicines that can treat rare diseases in a way that I don’t think anybody ever envisaged was possible four to five years ago, Maraganore said.
Alnylam’s laboratory innovation resulted in a major payoff: In January, Genzyme’s parent company, Sanofi SA, invested $700 million in Alnylam, just a few weeks after paying the company a $7 million milestone reward.
The enthusiasm for this new way was reflected in the first initial public offering from a Massachusetts company in 2014: Shares of Dicerna Therapeutics Inc. in Watertown, which also works in the RNAi space, jumped a whopping 207 percent on their first day of trading in late January.
Alnylam itself spent $175 million in January to buy a Merck subsidiary, Sirna Therapeutics, which works on RNA technologies.
Alnylam’s first target is a group of life-threatening diseases called amyloidosis, in which abnormal proteins build up in one or more organ systems and can lead to widespread failures in the body. The diseases are caused by proteins whose production can be turned off via RNAi. A late-stage clinical trial started at the end of last year and is expected to be completed in about three years.
Alnylam is also testing its RNAi injections in patients with hemophilia, the bleeding disorder, which is caused in part by a single malevolent protein.
Other companies are trying different delivery approaches. RXi Pharmaceuticals, of Westborough, has developed a direct injection delivery method — instead of wrapping the RNAi in a fatty ball — and is concentrating on diseases it can reach using needles, such as skin conditions, said Geert Cauwenbergh, the company’s chief executive.
Academic researchers are also still pushing the technology forward, hoping to deliver more effective drugs in a more targeted fashion.
At the Massachusetts Institute of Technology, researchers this month succeeded in making a more efficient delivery system using less RNAi than needed in previous approaches.
“This is the most potent yet,” associate professor Daniel Anderson said of his new delivery system, which encases the RNAi in tiny nanoparticles coated in fat and a specially designed polymer.
The nanoparticles are also specific, meaning they enter only the cells that make the protein they want to target — and not other cells. For now, Anderson is targeting those particles at the liver, where many disease proteins are made.
“The liver is an important therapeutic target,” Anderson said. “There are a lot of important diseases that can be affected by delivering RNA to the liver.”
Anderson said he hopes to be able to deliver RNAi to other organs, including the brain.
He also is working to turn off multiple genes at once. He has already shown that it is possible to have one nanoparticle of RNAi turn off 10 or more genes, he said. This ability will be crucial for fighting complex diseases that are the product of many genes working together.
There is a lot to learn about RNAi before it can reach its full potential in patients, Zamore said.
RNAi disrupts a 300-million-year-old pathway shared by bacteria, chickens, and humans, he said. With such power comes risk — although so far, there have been no major safety concerns with Alnylam’s RNAi delivery system, Zamore said, and side effects have been manageable.
But more clinical trials will be needed to get the balance right between side effects and helping patients get the most benefit from the drug, said Zamore, a founding member of Alnylam.
“With any of those really horrible diseases, patients are willing to try anything,” Zamore said, because often major drug companies had viewed those conditions as too difficult to treat.
Muriel Finkel, an advocate and founder of Amyloidosis Support Groups Inc., said she is thrilled that Alnylam is making progress against amyloidosis, a disease that can first rob people of their memories and then their lives.
“It’s huge, because it gives hope,” Finkel said.
Karen Weintraub can be reached at firstname.lastname@example.org.