Improving cancer immunotherapy by controlling RNA expression

Gene therapy has become one of the hottest areas of biotech research. Some gene therapies, like Spark Therapeutics’ eye drug Luxturna, deliver healthy genes to replace mutated ones, while others, such as Alnylam Pharmaceuticals’ RNA interference therapy Onpattro, work by silencing disease-causing genes. But controlling the strength and timing of gene expression with these therapies has proven challenging, especially when RNA is the central mechanism at work.

Massachusetts Institute of Technology scientists have now found a way to control RNA via a gene "circuit," which they believe will ensure patients get the desired dose of therapeutic protein, according to a new study published in Nature Chemical Biology. The researchers are already applying the approach to cancer immunotherapy.

Messenger RNA, or mRNA, could offer many advantages in gene therapy. It carries genetic information from DNA to ribosomes, where it instructs protein expression. It also has a limited lifetime, and unlike DNA, it isn’t permanently incorporated into a cell’s genome. Researchers and investors alike have become enamored of some players in the mRNA field, most notably biotech unicorn Moderna Therapeutics, which has 21 such candidates in development across several therapeutic areas.

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For their mRNA delivery method, the MIT scientists applied synthetic biology technology that allowed them to program synthetic "DNA circuits," they said in a statement. The circuits consist of a single strand of RNA that carries genetic information for the therapeutic proteins as well as RNA-binding proteins.

“Due to the dynamic nature of replication, the circuits’ performance can be tuned to allow different proteins to express at different times, all from the same strand of RNA,” Jacob Becraft, a lead author of the study, said in the statement.

These RNA-binding proteins act as “switches” of gene transcription that can be turned on or off by using small-molecule drugs. In their study, the researchers showed that the antibiotic doxycycline can repress, promote or prolong RNA gene expression as it either stabilizes or destabilizes the interaction between RNA and RNA-binding proteins.

MIT’s synthetic biologists have a history of utilizing gene circuits. Senti Bio, a 2018 Fierce 15 winner that was co-founded by MIT scientist Timothy Lu, is working on adding genetic circuits to cell therapies so that they can sense the tumor microenvironment and locate tumors, therefore eliciting a localized immune response. Lu and colleagues had previously adapted the electronics concept, known as “AND gates,” to gene circuits. For oncology, the technology could allow for a therapy to be activated only when two cancer biomarkers are present.

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Becraft and colleagues believe their mechanism can make gene therapies safer and more precise, and they’ve started a company called Strand Therapeutics to apply the approach to cancer immunotherapy. They plan to develop RNA circuits that can stimulate immune cells to specifically attack tumors that have spread to otherwise inaccessible parts of the body.

“The hope is to elicit an immune response which is able to pick up and treat the rest of the metastases throughout the body,” Becraft said. “If you’re able to treat one site of the cancer, then your immune system will take care of the rest, because you’ve now built an immune response against it.”