Delivering functional genes into cells to replace mutated genes, an approach known as gene therapy, holds potential for treating many types of diseases. Early gene therapy focused on DNA, but many scientists are now exploring the possibility of using RNA instead, which could improve safety and delivery.
In a study published today in Nature Chemical Biology, MIT biological engineers devised a method to regulate the expression of RNA once it gets into cells, allowing for precise control over the dose of protein that a patient receives. This technology could allow doctors to more accurately tailor treatment for individual patients, and it also offers a way to quickly turn the genes off, if necessary.
"We can control very discretely how different genes are expressed," says Jacob Becraft, an MIT graduate student. "Historically, gene therapies have encountered issues regarding safety, but with new advances in synthetic biology, we can create entirely new paradigms of 'smart therapeutics' that actively engage with the patient's own cells to increase efficacy and safety."
As a tool for gene therapy, DNA can be difficult to work with. When carried by synthetic nanoparticles, the particles must be delivered to the nucleus, which can be inefficient. Viruses are more efficient, but they can be immunogenic, difficult, and expensive to produce, and they often integrate their DNA into the cell's own genome, limiting their applicability in genetic therapies. Messenger RNA offers a more direct—and nonpermanent—way to alter cells' gene expression.
The researchers adapted synthetic biology principles, which allow for precise programming of synthetic DNA circuits, to RNA. Their new circuits consist of a single strand of RNA that includes genes for both the desired therapeutic proteins and RNA-binding proteins that control the expression of the therapeutic 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," Becraft says.
This allows the researchers to turn on the circuits at the right time by using "small molecule" drugs. When a drug is added to the cells, it can stabilize or destabilize the interaction between RNA and RNA-binding proteins. In a previous study, the researchers also showed that they could build cell-specificity into their circuits so that the RNA only becomes active in target cells.