Duke, MIT, and Stanford scientists create RNA technology that could improve genetic therapies

Jonathan S. said: Gutenberg, the scientist at MIT’s McGovern Institute who developed the technology with fellow McGovern Omar W.

As with many new biotechnologies, the invention is already starting to capture the attention of investors. The three groups are patenting similar versions of the technology. Each team hinted that RNA sensors could soon find their way into existing or newly formed biotech startups.

A limitation of experimental mRNA therapies is that they are usually triggered in any cell they can enter. But if an mRNA therapy contains instructions for a toxic cancer-killing protein, for example, it could wreak havoc outside the tumor. Chen said that including RNA sensors in treatments could prevent them from turning them off until the time is right.

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

This technology is based on harnessing a natural enzyme called ADAR that can change one letter in the genetic code of an RNA strand into another letter. Several biotech companies — including Cambridge companies EdiGene, Korro Bio and Wave Life Sciences — are still in the early stages of developing treatments that hijack the enzyme and reprogram it to treat genetic diseases by editing RNA.

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The RNA sensing technology also builds on ADAR’s editing ability, but with a different purpose: converting the genetic equivalent of a red traffic light into a green one.

Sensors are synthetic RNA molecules designed to mate with – and thus “sense” – naturally occurring RNA strands that are only found in certain types of cells or disease states. Natural and synthetic molecules intertwine almost perfectly except for a few mismatched code, which ADAR cannot resist stabilization. When the enzyme rushes in and releases it, it changes the genetic red light into a green light.

“You block something until you have the right conditions to open it or release it,” Guttenberg said. “It will just run exactly where we want it.”

Pairing the RNA sensors with a gene-editing tool like CRISPR can help ensure that only the desired cells make permanent changes, Abu Dayyeh said. If the treatment aims to alter the immune system’s T cells, for example, the RNA sensors can reduce the risk of inadvertently editing other parts of the body.

“I think it’s very interesting,” said Jacob Beecraft, CEO of Boston-based Strand Therapeutics, which was not involved in the studies. But Beecraft, who has developed his own way to turn mRNA treatments on or off, cautions that there may be “a number of challenges” in applying RNA probes to treatments.

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While the MIT and Stanford researchers initially focused on using the sensors in cells grown in test tubes, Duke’s 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 live animals.

“We approached it from a very basic research perspective,” Huang said. His lab tested this method on rodents as well as human brain samples left from epilepsy surgeries. “Once we had it, the implications for treatments and diagnosis were clear,” he said.

Huang hopes that using RNA sensing to better understand neuropsychiatric diseases could lead to gene therapies that target specific types of brain cells implicated in these conditions. “This may be a long-term goal, but we have some ideas on how to achieve that.”

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 to me is that you can keep the cell and the animal alive while you’re sensing,” he said.

The three teams of scientists who developed the 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 appeared in Nature Biotechnology later on October 27.

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Each group pointed out the finer details of how their RNA sensors were made or used, and all said they are working to improve the technology further, especially 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,” said Xiaojing J. Gao of Stanford, who developed the RNA sensor with one of his students, K. Eerik Kaseniit. .

Gao and Huang said they have received an influx of requests to learn more about the technology from other scientists, pharmaceutical companies and venture capital groups since publishing their papers in early October. Zhao said the Duke and Stanford groups decided to collaborate to establish a biotech company to develop the technology.

Abudayyeh and Gootenberg have already 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 sensor technology will end up “is being determined,” Gutenberg said.

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

Ryan Cross can be reached at [email protected] Follow him on Twitter Tweet embed.


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