Scientists from Duke, MIT, and Stanford have independently devised a molecular trick that could help make genetic therapies safer and more effective. The technology, which was disclosed in three separate papers published recently, could help ensure that treatments based on DNA or RNA are only activated once they reach the right part of the body.
The researchers are already envisioning a bevy of applications in basic research, diagnostics, and therapeutics. Their inventions — dubbed “programmable RNA sensors” — could lead to more precise cancer drugs that kill tumors but spare healthy cells, they said. Or the sensors could be paired with CRISPR gene editing therapies to reduce the chance of unwanted changes to the genome, they added.
“It’s about making these therapies much smarter and programmable,” said Jonathan S. Gootenberg, a scientist at the McGovern Institute of MIT who codeveloped the technology with his McGovern colleague Omar O. Abudayyeh and Fei Chen from the Broad Institute of MIT and Harvard.
As with many new biotechnologies, the invention has already started to attract the attention of investors. All three groups are filing patents on similar versions of the technology. And each team hinted that the RNA sensors could soon find their way into existing or newly formed biotech startups.
One limitation of experimental messenger RNA therapies is that they are typically turned on in any cell they can get into. But if an mRNA therapy carried instructions for a toxic cancer-killing protein, for instance, it could wreak havoc outside of a tumor. Embedding RNA sensors in the therapies could keep them turned off until the moment is right, Chen said.
The technology relies on harnessing a natural enzyme called ADAR that can change one letter in an RNA strand’s genetic code into another letter. Several biotech companies — including Cambridge firms EdiGene, Korro Bio, and Wave Life Sciences — are in the early stages of developing therapies that hijack and reprogram the enzyme to treat genetic diseases by editing RNA.
RNA sensing technology also relies on ADAR’s editing ability, but for a different purpose: to turn the genetic equivalent of a red traffic light into a green one.
The sensors are synthetic RNA molecules designed to pair with — and thus “sense” — naturally occurring RNA strands that are only found in particular kinds of cells or particular disease states. The natural and synthetic molecules mesh nearly perfectly except for a bit of mismatched code, which ADAR can’t resist fixing. When the enzyme swoops in and makes its edit, it changes the genetic red light into a green light.
“You’re blocking something until you have the right conditions to unlock or unleash it,” Gootenberg said. “It will only be turned on exactly where we want.”
Pairing RNA sensors with a gene editing tool like CRISPR could help ensure that permanent changes are only made in desired cells, Abudayyeh said. If a therapy is intended to alter the T cells of the immune system, for instance, RNA sensors could reduce the risk of other parts of the body from being inadvertently edited.“I think it’s very interesting,” said Jacob“I think it’s very interesting,” said Jacob
“I think it’s very interesting,” said Jacob Becraft, chief executive of the Boston-based mRNA therapy startup Strand Therapeutics, who wasn’t involved in the studies. But Becraft, who has developed his own method for turning mRNA therapies on or off, cautions that there could be “a number of challenges” in applying the RNA sensors to therapies.
While the MIT and Stanford researchers initially focused on using the sensors in cells grown in test tubes, the Duke team, led by neuroscientist Dr. Josh Huang, took the technology a step further. His lab developed RNA sensors as a way to identify, study, and control different types of brain cells in living animals.
“We approached it from a very fundamental basic research perspective,” Huang said. His lab tested the method in rodents as well as human brain samples leftover from epilepsy surgeries. “Once we succeeded, the implications for therapies and diagnostics were obvious,” he said.
Huang hopes that using RNA sensing to better understand neurological and psychiatric diseases could lead to genetic therapies that target specific types of brain cells implicated in the conditions. “That is probably a longer-term goal, but we have some ideas about how to get there.”
Qiaobing Xu, a professor of bioengineering at Tufts University who wasn’t involved in the new studies, is excited about using RNA sensors as new research tools. “The most interesting thing to me is that you can keep the cell and animal alive while you do the sensing,” he said.
The three teams of scientists developing RNA sensors said that they came up with the invention independently. The Duke group’s paper was published in Nature on Oct. 5 and the Stanford team’s paper was published in Nature Biotechnology the same day. The MIT team’s paper appeared in Nature Biotechnology later on Oct. 27.
Each group pointed to subtleties in how they made or used their RNA sensors, and all said they are working to improve the technology further, especially for medical applications.
“The fundamental design is exactly the same, and that actually bodes very well for the system. The key differences are in the details,” said Xiaojing J. Gao from Stanford, who developed an RNA sensor with one of his students, K. Eerik Kaseniit. The lab has also applied the technique to plants.
Gao and Huang said they’ve had an influx of requests to learn more about the technology from other scientists, drug companies, and venture capital groups since their papers were published in early October. The Duke and Stanford groups have decided to team up on founding a biotech company to advance the technology, Gao said.
Abudayyeh and Gootenberg have already cofounded several biotech companies, including Sherlock Biosciences, Proof Diagnostics, Moment Biosciences, and Tome Biosciences, and Chen has cofounded a firm called Curio Biosciences. But where, exactly, the RNA sensor technology will end up is “to be determined,” Gootenberg said.
“We’re excited to see how people use it,” Chen said. “It’s a cool tool, and there’s just a myriad of uses, and we probably haven’t thought of the coolest use of the technology yet. That’s probably going to come from someone else who sees it and is inspired by it.”