Scientists from Duke, MIT and Stanford are developing RNA technology that could improve gene therapies

“It’s about making these therapies much smarter and much more programmable,” said Jonathan S. Gootenberg, a scientist at McGovern Institute of MIT who developed the technology with his McGovern colleague Omar O. Abudayyeh and Fei Chen of the Broad Institute of MIT and Harvard developed.

As with many new biotechnologies, the invention has already begun to attract the attention of investors. All three groups are filing patents for 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.

A limitation of experimental messenger RNA therapies is that they are typically turned on in every cell they can enter. But if mRNA therapy contained instructions for, say, a toxic cancer-killing protein, it could wreak havoc outside of a tumor. Embedding RNA sensors in the therapies could keep them turned off until the right moment, Chen said.

Fei Chen, a researcher at MIT’s and Harvard’s Broad Institute, is curious to see what other scientists are doing with the RNA sensing technology he helped develop.Casey Atkins/Casey Atklin Photography

The technology is based on the use of a natural enzyme called ADAR, which can convert one letter in the genetic code of a strand of RNA 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 would hijack and reprogram the enzyme to treat genetic diseases by editing RNA.

RNA sensing technology also draws on ADAR’s editing ability, but for a different purpose: turning the genetic equivalent of a red light into a green one.

The sensors are synthetic RNA molecules designed to pair with naturally occurring RNA strands – and thus “sense” – that are only found in certain types of cells or certain disease states. The natural and synthetic molecules mesh almost perfectly, save for some mismatched code that ADAR can’t resist fixing. When the enzyme steps in and does its editing, it changes the genetic red light to a green light.

“You block something until you have the right conditions to release or unblock it,” Gootenberg said. “It only turns on exactly where we want it to.”

Pairing RNA sensors with a gene-editing tool like CRISPR could help ensure permanent changes are made only in the desired cells, Abudayyeh said. For example, if a therapy is designed to alter the immune system’s T cells, RNA sensors could reduce the risk of other parts of the body being unintentionally processed.

“I find it very interesting,” said Jacob Becraft, chief executive officer of Boston-based mRNA therapy startup Strand Therapeutics, who was not involved with the studies. But Becraft, who developed his own method of turning mRNA therapies on and off, warns that there may 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 takes technology a step further. His lab developed RNA sensors to identify, study, and monitor different types of brain cells in living animals.

“We approached it from a very basic fundamental research perspective,” Huang said. His lab tested the method on rodents as well as human brain samples left over from epilepsy surgeries. “Once we were successful, the implications for therapies and diagnostics were obvious,” he said.

Huang hopes that using RNA recognition to better understand neurological and psychiatric disorders could lead to gene therapies that target specific types of brain cells involved in the disorders. “That’s probably a longer-term goal, but we have some ideas on how to get there.”

Qiaobing Xu, a professor of bioengineering at Tufts University who was not involved in the new studies, is excited about using RNA sensors as new research tools. “The most interesting thing for me is that you can keep the cell and the animal alive while doing the perception,” he said.

The three teams of scientists developing RNA sensors said they came up with the invention independently. The Duke group’s paper was published in Nature on October 5, and the Stanford team’s paper was published in Nature Biotechnology on the same day. The MIT team’s paper later appeared in Nature Biotechnology on October 27.

Each group pointed out intricacies in making or using their RNA sensors, and all said they are working to further improve the technology, particularly for medical applications.

“The basic design is exactly the same, and that actually bodes well for the system. The main differences are in the details,” says 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 have had an influx of requests to learn more about the technology from other scientists, pharmaceutical companies and venture capital groups since the release of their papers in early October. The Duke and Stanford groups have decided to form a biotech company together to advance the technology, Gao said.

Abudayyeh and Gootenberg have previously co-founded several biotech companies, including Sherlock Biosciences, Proof Diagnostics, Moment Biosciences and Tome Biosciences, and Chen co-founded a company called Curio Biosciences. But where exactly the RNA sensing technology will end up “has yet to be determined,” Gootenberg said.

“We’re excited to see how people use it,” Chen said. “It’s a cool tool and there are countless uses for it, and we probably haven’t thought of the coolest use of the technology yet. That’s probably coming from someone else seeing it and being inspired by it.”

Ryan Cross can be reached at [email protected] Follow him on Twitter @RLCscienceboss.


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