Scientists at Duke, MIT and Stanford create RNA technology that could improve gene therapy

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

Like many new biotechnologies, the invention has begun to grab investors’ attention. All three groups are patenting similar versions of the technology. Each team hinted that RNA sensors could soon find their way into existing or newly established biotech startups.

One limitation of experimental messenger RNA therapies is that they are typically turned on in any cell they can enter. But if, for example, mRNA therapy carries instructions for a toxic anti-cancer protein, it could wreak havoc beyond the tumor. Embedding RNA sensors in therapies could keep them off until the time is right, Chen said.

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

The technology relies on harnessing a natural enzyme called ADAR, which can change one letter of the genetic code of an RNA strand into another. Several biotech companies, including Cambridge firm EdiGene, Korro Bio and Wave Life Sciences, are in the early stages of developing therapies that edit RNA to hijack and reprogram enzymes to treat genetic diseases.

RNA sensing technology also relies on ADAR’s editing capabilities, but for a different purpose: to turn the genetic equivalent of a red traffic light into a green traffic light.

These sensors are synthetic RNA molecules designed to pair with, and thus “sensize,” naturally occurring RNA strands that are only present in certain kinds of cells or in certain disease states. Natural and synthetic molecules fit together almost perfectly, except for a few mismatched codes, ADAR can’t resist fixing. When the enzyme pops in and makes an edit, it turns the genetic red light into a green light.

“You block something until you have the right conditions to unlock or release it,” Gootenberg said. “It will only open where we want it to be.”

Pairing RNA sensors with gene-editing tools like CRISPR could help ensure permanent changes are made only in the desired cells, Abudayyeh said. For example, if a therapy is aimed at altering the immune system’s T cells, RNA sensors could reduce the risk of inadvertent editing elsewhere in the body.

“I thought it was interesting,” said Jacob Becraft, CEO of Boston-based mRNA therapy startup Strand Therapeutics, who was not involved in the studies. But Becraft, who has developed his own ways to turn mRNA therapy on or off, warns that there could be “many challenges” in applying RNA sensors to therapy.

While researchers at MIT and Stanford initially focused on using sensors in cells grown in test tubes, 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 basic fundamental research perspective,” Huang said. His lab tested the approach on rodents as well as human brain samples left over from epilepsy surgery. “Once we were successful, the implications for treatment and diagnosis were clear,” he said.

Huang hopes to use RNA sensing to better understand neurological and psychiatric diseases, which could lead to gene therapy targeting specific types of brain cells involved in these diseases. “It may be a long-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 study, is excited about using RNA sensors as a new research tool. “The most interesting thing to me is that you can keep cells and animals alive while sensing,” he said.

The three teams of scientists who developed the RNA sensor said they independently came up with the invention. The Duke team’s paper was published in the journal Nature in October. 5 and the Stanford team’s paper were published in Nature Biotechnology on the same day. The MIT team’s paper was published in Nature Biotechnology later in October. 27.

Each group pointed to subtleties in how they made or used the RNA sensor, and all said they were working to further improve the technology, especially for medical applications.

“The basic design is exactly the same, which actually bodes well for the system. The key difference is in the details,” said Xiaojing J. Gao of Stanford University, who developed an RNA sensor with his student K. Eerik Kaseniit. The lab has also applied the technology to plants.

Gao and Huang said that since their paper was published in early October, they have received more requests for the technology from other scientists, pharmaceutical companies and venture capital groups. Gao said the Duke and Stanford teams decided to collaborate on a biotech company to advance the technology.

Abudayyeh and Gootenberg have co-founded several biotech companies, including Sherlock Biosciences, Proof Diagnostics, Moment Biosciences and Tome Biosciences, and Chen also co-founded a company called Curio Biosciences. But exactly where the RNA sensor technology will end up “remains 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, and we probably haven’t thought of the coolest use for this technology. It could be from other people who see it and are inspired.”

Ryan Cross can be contacted at him on twitter @RLCscienceboss.

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